|
1
|
Zhu S, Fu K, Li S, Yang C, Pan C, Wang X, Wang F, Yu X, To KKW, Fu L. Cardiotoxicity of small-molecule kinase inhibitors in cancer therapy. Exp Hematol Oncol 2025; 14:68. [PMID: 40346640 PMCID: PMC12063284 DOI: 10.1186/s40164-025-00660-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 04/22/2025] [Indexed: 05/11/2025] Open
Abstract
Cancer is one of the leading causes of death worldwide. Recent advances in precision oncology have enabled many specific cancer patient populations to respond well and achieve longer survival with small-molecule kinase inhibitors, which have become a new therapeutic strategy for tumors. Since 2001, the Food and Drug Administration has approved 108 and 63 new anticancer drugs for treating solid tumors and hematological malignancies, respectively, 89 of which belong to the large group of small-molecule kinase inhibitors (SMKIs). Compared to conventional chemotherapeutic agents such as cyclophosphamide, doxorubicin, and 5-FU, SMKIs offer better efficacy with fewer toxic side effects. Nevertheless, with the development of more novel SMKIs and their wider clinical application to a larger population of cancer patients, variable degrees of cardiotoxic adverse events have emerged for some SMKIs during cancer therapy. This review comprehensively summarizes the most updated progress in the cardiotoxicity of SMKIs in cancer therapy and discusses the new findings and mechanisms, which will provide emerging strategies for the prevention of cardiotoxicity caused by small molecule targeted drugs and the design of the next generation of low cardiotoxicity targeted drugs.
Collapse
Affiliation(s)
- Shuangli Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Kai Fu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Sijia Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Chuan Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Can Pan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Xueping Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Fang Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Xiyong Yu
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangdong, Guangzhou Medical University, Guangzhou, 511436, China
| | - Kenneth Kin Wah To
- School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - Liwu Fu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China.
| |
Collapse
|
|
2
|
Lopez KE, Meola DM, Camarda ND, Upshaw JN, Jaffe IZ, London CA, Yang VK. Effect of the Vascular Endothelial Growth Factor Inhibitor Toceranib on Cardiac Function and Endothelial Dysfunction Biomarkers in Dogs With Cancer. J Vet Intern Med 2025; 39:e70115. [PMID: 40375566 PMCID: PMC12081826 DOI: 10.1111/jvim.70115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 04/17/2025] [Accepted: 04/17/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Hypertension is documented in dogs with cancer receiving toceranib, but no studies have evaluated left ventricular (LV) systolic function and biomarkers of endothelial function. OBJECTIVES To characterize changes in echocardiographic variables and biomarkers of endothelial function in dogs treated with toceranib. ANIMALS Twenty-six client-owned dogs with no evidence of pre-existing cardiac disease or systemic hypertension are receiving a single agent toceranib for cancer treatment. METHODS Dogs were enrolled in this prospective observational study with study visits at baseline, 1, 3, and 5 months after starting toceranib for echocardiographic exams, blood and urine collection, and blood pressure measurements, with an additional blood pressure obtained 2 weeks after starting toceranib. Serum markers of vascular endothelial function (VEGF, endothelin-1, platelet derived growth factor [PDGF], prostacyclin, cyclic guanosine monophosphate [cGMP]) and urinary nitrate were evaluated with ELISA. RESULTS Dogs were enrolled between 2019 and 2023. Systolic blood pressure increased 2 weeks after initiating toceranib treatment (p = 0.009). Serum prostacyclin concentration was lower after 1 month of treatment (mean 98.8 pg/mL vs. 140.0 pg/mL at baseline, p = 0.03), and serum VEGF concentration was higher after 3 months of treatment (mean of 247.8 pg/mL vs. 135.4 pg/mL at baseline, p = 0.01). Global longitudinal strain (GLS) decreased at the five-month time point (mean -14.5% vs. -15.7% at baseline, p = 0.048) with no significant change in LV fractional shortening by M-mode or ejection fraction by Simpson's method of discs. CONCLUSIONS Dogs treated with toceranib might have higher systemic blood pressure associated with changes in VEGF and prostacyclin and decreased systolic function.
Collapse
Affiliation(s)
- Katherine E. Lopez
- Cummings School of Veterinary Medicine at Tufts UniversityNorth GraftonMassachusettsUSA
| | - Dawn M. Meola
- Cummings School of Veterinary Medicine at Tufts UniversityNorth GraftonMassachusettsUSA
| | - Nicholas D. Camarda
- Molecular Cardiology Research InstituteTufts Medical CenterBostonMassachusettsUSA
- Tufts Graduate School of Biomedical SciencesBostonMassachusettsUSA
| | - Jenica N. Upshaw
- Division of CardiologyTufts Medical CenterBostonMassachusettsUSA
| | - Iris Z. Jaffe
- Molecular Cardiology Research InstituteTufts Medical CenterBostonMassachusettsUSA
- Tufts Graduate School of Biomedical SciencesBostonMassachusettsUSA
| | - Cheryl A. London
- Cummings School of Veterinary Medicine at Tufts UniversityNorth GraftonMassachusettsUSA
| | - Vicky K. Yang
- Cummings School of Veterinary Medicine at Tufts UniversityNorth GraftonMassachusettsUSA
| |
Collapse
|
|
3
|
Solomon AD, Dabral S, Brajesh RG, Day BW, Juric M, Zielonka J, Bosnjak ZJ, Pant T. Understanding the Mechanisms of Chemotherapy-Related Cardiotoxicity Employing hiPSC-Derived Cardiomyocyte Models for Drug Screening and the Identification of Genetic and Epigenetic Variants. Int J Mol Sci 2025; 26:3966. [PMID: 40362211 PMCID: PMC12071959 DOI: 10.3390/ijms26093966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/10/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Chemotherapy-related cardiotoxicity (CTRTOX) is a profound and common side effect of cancer-based therapy in a subset of patients. The underlying factors and the associated mechanisms contributing to severe toxicity of the heart among these patients remain unknown. While challenges remain in accessing human subjects and their ventricular cardiomyocytes (CMs), advancements in human induced pluripotent stem cell (hiPSC)-technology-based CM differentiation protocols over the past few decades have paved the path for iPSC-based models of human cardiac diseases. Here, we offer a detailed analysis of the underlying mechanisms of CTRTOX. We also discuss the recent advances in therapeutic strategies in different animal models and clinical trials. Furthermore, we explore the prospects of iPSC-based models for identifying novel functional targets and developing safer chemotherapy regimens for cancer patients that may be beneficial for developing personalized cardioprotectants and their application in clinical practice.
Collapse
Affiliation(s)
- Abhishikt David Solomon
- Adams School of Dentistry, Oral and Craniofacial Biomedicine, University of North Carolina, Chapel Hill, NC 27599, USA;
| | - Swarna Dabral
- Maharishi Markandeshwar College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, India;
| | - Raman Gulab Brajesh
- Department of Biomedical Engineering and Bioinformatics, Swami Vivekanand Technical University, Durg 491107, India;
| | | | - Matea Juric
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; (M.J.); (J.Z.)
| | - Jacek Zielonka
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; (M.J.); (J.Z.)
| | - Zeljko J. Bosnjak
- Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA;
| | - Tarun Pant
- Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA;
- Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| |
Collapse
|
|
4
|
Yang Z, Wan J, Zhang X, Mei J, Hao H, Liu S, Yi Y, Jiang M, He Y. Baicalin reduces sunitinib-induced cardiotoxicity in renal carcinoma PDX model by inhibiting myocardial injury, apoptosis and fibrosis. Front Pharmacol 2025; 16:1563194. [PMID: 40264678 PMCID: PMC12011809 DOI: 10.3389/fphar.2025.1563194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 03/24/2025] [Indexed: 04/24/2025] Open
Abstract
Sunitinib (SU), a multi-targeted tyrosine kinase inhibitor, has anticancer function but its clinical use is often limited by cardiovascular complications. Baicalin (BA) has demonstrated various pharmacological activities including antioxidant, anti-inflammatory and antiviral properties, but its potential roles in SU-induced cardiotoxicity have not been reported. In this study, we aimed to investigate the effect of BA in SU-induced cardiotoxicity in vivo by using renal carcinoma patient-derived xenograft (PDX) model. Female Nod Scid mice with renal carcinoma PDX were treated with vehicle, SU (50 mg/kg/d), BA (100 mg/kg/d), or BA combined with SU for 6 weeks. The tumor volume and weight of tumor-bearing mice were measured, and cardiovascular functions were evaluated by testing the Heart index and blood biochemical indicators, and by hematoxylin and eosin (H&E), Masson and Tunel staining. The results showed that SU therapy and combination therapy effectively inhibited the growth of renal tumors. Combination therapy inhibited SU-induced increase of creatine kinase (CK) and lactate dehydrogenase (LDH), and ameliorated the heart parameters. Moreover, BA effectively protected SU-induced cardiac dysfunction by decreasing injury, apoptosis, and fibrosis. Collectively, our results demonstrate that BA can be as a potential cardioprotective approach for cardiovascular complications during SU regimen.
Collapse
Affiliation(s)
- Zefu Yang
- Cardiovascular Medicine Department of Nanhai District People’s Hospital, Foshan, Guangdong, China
- Cardiovascular Medicine Department of The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China
| | - Jianping Wan
- Electrophysiology Department of The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China
| | - Xinjin Zhang
- Cardiovascular Center, Affiliated Hospital of Yunnan University, Kunming, China
| | - Jiaqi Mei
- Department of Hematology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Hua Hao
- Department of Pathology, Yangpu District Central Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Sibo Liu
- The Queen MARY school, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yun Yi
- Center of Biobank, Nanchang University Second Affiliated Hospital, Jiangxi Medical College, Nanchang, China
| | - Meixiu Jiang
- The Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yuanqiao He
- Center of Laboratory Animal Science, Nanchang University, Nanchang, China
- Jiangxi Province Key Laboratory of Laboratory Animal, Nanchang, China
- Nanchang Royo Biotechnology, Nanchang, China
| |
Collapse
|
|
5
|
Zhou L, Zhu X, Lei S, Wang Y, Xia Z. The role of the ER stress sensor IRE1 in cardiovascular diseases. Mol Cell Biochem 2025; 480:683-691. [PMID: 38717685 DOI: 10.1007/s11010-024-05014-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/18/2024] [Indexed: 02/19/2025]
Abstract
Despite enormous advances in the treatment of cardiovascular diseases, including I/R injury and heart failure, heart diseases remain a leading cause of mortality worldwide. Inositol-requiring enzyme 1 (IRE1) is an evolutionarily conserved sensor endoplasmic reticulum (ER) transmembrane protein that senses ER stress. It manages ER stress induced by the accumulation of unfolded/misfolded proteins via the unfolded protein response (UPR). However, if the stress still persists, the UPR pathways are activated and induce cell death. Emerging evidence shows that, beyond the UPR, IRE1 participates in the progression of cardiovascular diseases by regulating inflammation levels, immunity, and lipid metabolism. Here, we summarize the recent findings and discuss the potential therapeutic effects of IRE1 in the treatment of cardiovascular diseases.
Collapse
Affiliation(s)
- Lu Zhou
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xizi Zhu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shaoqing Lei
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yafeng Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan, China.
| | - Zhongyuan Xia
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
| |
Collapse
|
|
6
|
Chen M, Xue J, Wang M, Yang J, Chen T. Cardiovascular Complications of Pan-Cancer Therapies: The Need for Cardio-Oncology. Cancers (Basel) 2023; 15:cancers15113055. [PMID: 37297017 DOI: 10.3390/cancers15113055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/28/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023] Open
Abstract
It is more likely that a long-term survivor will have both cardiovascular disease and cancer on account of the progress in cancer therapy. Cardiotoxicity is a well-recognized and highly concerning adverse effect of cancer therapies. This side effect can manifest in a proportion of cancer patients and may lead to the discontinuation of potentially life-saving anticancer treatment regimens. Consequently, this discontinuation may adversely affect the patient's survival prognosis. There are various underlying mechanisms by which each anticancer treatment affects the cardiovascular system. Similarly, the incidence of cardiovascular events varies with different protocols for malignant tumors. In the future, comprehensive cardiovascular risk assessment and clinical monitoring should be considered for cancer treatments. Baseline cardiovascular evaluation risk should be emphasized prior to initiating clinical therapy in patients. Additionally, we highlight that there is a need for cardio-oncology to avoid or prevent cardiovascular side effects. Cardio-oncology service is based on identifying cardiotoxicity, developing strategies to reduce these toxicities, and minimizing long-term cardiotoxic effects.
Collapse
Affiliation(s)
- Mengjia Chen
- Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jianing Xue
- Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Maoling Wang
- Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Junyao Yang
- Department of Laboratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ting Chen
- Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
- Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou 310058, China
| |
Collapse
|
|
7
|
Drăgan A, Sinescu I. The Role of the Cardiac Biomarkers in the Renal Cell Carcinoma Multidisciplinary Management. Diagnostics (Basel) 2023; 13:1912. [PMID: 37296764 PMCID: PMC10253077 DOI: 10.3390/diagnostics13111912] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/27/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Renal cell carcinoma, an aggressive malignancy, is often incidentally diagnosed. The patient remains asymptomatic to the late stage of the disease, when the local or distant metastases are already present. Surgical treatment remains the choice for these patients, although the plan must adapt to the characteristics of the patients and the extension of the neoplasm. Systemic therapy is sometimes needed. It includes immunotherapy, target therapy, or both, with a high level of toxicity. Cardiac biomarkers have prognosis and monitoring values in this setting. Their role in postoperative identification of myocardial injury and heart failure already have been demonstrated, as well as their importance in preoperative evaluation from the cardiac point of view and the progression of renal cancer. The cardiac biomarkers are also part of the new cardio-oncologic approach to establishing and monitoring systemic therapy. They are complementary tests for assessment of the baseline toxicity risk and tools to guide therapy. The goal must be to continue the treatment as long as possible with the initiation and optimisation of the cardiological treatment. Cardiac atrial biomarkers are reported to have also antitumoral and anti-inflammatory properties. This review aims to present the role of cardiac biomarkers in the multidisciplinary management of renal cell carcinoma patients.
Collapse
Affiliation(s)
- Anca Drăgan
- Department of Cardiovascular Anaesthesiology and Intensive Care, Prof. C.C. Iliescu Emergency Institute for Cardiovascular Diseases, 258 Fundeni Road, 022328 Bucharest, Romania
| | - Ioanel Sinescu
- Department of Urological Surgery, Dialysis and Kidney Transplantation, Fundeni Clinical Institute, 258 Fundeni Road, 022328 Bucharest, Romania;
- Department of Uronephrology, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| |
Collapse
|
|
8
|
Zelmat Y, Conte C, Noize P, Vabre C, Pajiep M, Lafaurie M, Lapeyre-Mestre M, Despas F. Incidence of heart failure following exposure to a protein kinase inhibitor, a French population-based study. Br J Clin Pharmacol 2023; 89:1338-1348. [PMID: 36285576 DOI: 10.1111/bcp.15576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/10/2022] [Accepted: 10/14/2022] [Indexed: 11/28/2022] Open
Abstract
AIMS Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF. METHODS Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long-term HF-related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias. RESULTS Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67-3.52), dasatinib (aHR = 2.22, 95% CI 1.42-3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69-2.64), crizotinib (aHR = 1.71, 95% CI 1.07-2.72), everolimus (aHR = 1.45, 95% CI 1.26-1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01-1.86). Sensitivity analyses were consistent with our primary analysis. CONCLUSIONS The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses.
Collapse
Affiliation(s)
- Yoann Zelmat
- Medical and Clinical Pharmacology Unit, University Hospital Centre Toulouse, Toulouse, France
| | - Cécile Conte
- Medical and Clinical Pharmacology Unit, University Hospital Centre Toulouse, Toulouse, France.,Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France
| | - Pernelle Noize
- Bordeaux University, INSERM, BPH, U1219, Bordeaux, France.,Department of Medical and Clinical Pharmacology, Bordeaux University Hospital, Bordeaux, France
| | - Clémentine Vabre
- Medical and Clinical Pharmacology Unit, University Hospital Centre Toulouse, Toulouse, France.,Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France
| | - Marie Pajiep
- Medical and Clinical Pharmacology Unit, University Hospital Centre Toulouse, Toulouse, France.,Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France
| | - Margaux Lafaurie
- Medical and Clinical Pharmacology Unit, University Hospital Centre Toulouse, Toulouse, France.,Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France
| | - Maryse Lapeyre-Mestre
- Medical and Clinical Pharmacology Unit, University Hospital Centre Toulouse, Toulouse, France.,Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France
| | - Fabien Despas
- Medical and Clinical Pharmacology Unit, University Hospital Centre Toulouse, Toulouse, France.,Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France.,Clinical Investigation Centre 1436, University Hospital Centre Toulouse, Toulouse cedex 9, France.,Equipe Pharmacologie en Population (Population Pharmacology Team), cohorteS, biobanqueS, PEPPS, Toulouse University, Toulouse, France
| |
Collapse
|
|
9
|
Franczyk B, Rysz J, Ławiński J, Ciałkowska-Rysz A, Gluba-Brzózka A. Cardiotoxicity of Selected Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Renal Cell Carcinoma. Biomedicines 2023; 11:181. [PMID: 36672689 PMCID: PMC9855533 DOI: 10.3390/biomedicines11010181] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/28/2022] [Accepted: 01/03/2023] [Indexed: 01/13/2023] Open
Abstract
Renal cell carcinoma (RCC) is one of the most frequent malignant neoplasms of the kidney. The therapeutic options available for the treatment of advanced or metastatic RCC include vascular endothelial growth factor receptor (VEGFR)-targeted molecules, for example, tyrosine kinase inhibitors (TKI). Various VEGFR-TKIs proved to be effective in the treatment of patients with solid tumours. The combination of two drugs may prove most beneficial in the treatment of metastatic RCC; however, it also enhances the risk of toxicity compared to monotherapy. Specific VEGFR-TKIs (e.g., sunitinib, sorafenib or pazopanib) may increase the rate of cardiotoxicity in metastatic settings. VEGF inhibitors modulate multiple signalling pathways; thus, the identification of the mechanism underlying cardiotoxicity appears challenging. VEGF signalling is vital for the maintenance of cardiomyocyte homeostasis and cardiac function; therefore, its inhibition can be responsible for the reported adverse effects. Disturbed growth factor signalling pathways may be associated with endothelial dysfunction, impaired revascularization, the development of dilated cardiomyopathy, cardiac hypertrophies and altered peripheral vascular load. Patients at high cardiovascular risk at baseline could benefit from clinical follow-up in the first 2-4 weeks after the introduction of targeted molecular therapy; however, there is no consensus concerning the surveillance strategy.
Collapse
Affiliation(s)
- Beata Franczyk
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 113 Żeromskiego Street, 90-549 Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 113 Żeromskiego Street, 90-549 Lodz, Poland
| | - Janusz Ławiński
- Department of Urology, Institute of Medical Sciences, Medical College of Rzeszow University, 35-055 Rzeszow, Poland
| | | | - Anna Gluba-Brzózka
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 113 Żeromskiego Street, 90-549 Lodz, Poland
| |
Collapse
|
|
10
|
Nomoto N, Tate S, Arai M, Iizaka S, Mori C, Sakurai K. Pretreatment Nutritional Status in Combination with Inflammation Affects Chemotherapy Interruption in Women with Ovarian, Fallopian Tube, and Peritoneal Cancer. Nutrients 2022; 14:5183. [PMID: 36501212 PMCID: PMC9741349 DOI: 10.3390/nu14235183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/11/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Discontinuing chemotherapy worsens cancer prognosis. This study aimed to investigate the relationship between nutritional status at the start of chemotherapy and chemotherapy discontinuation in patients with ovarian, fallopian tube, and primary peritoneal cancer. METHODS This was a retrospective cohort study. One hundred and forty-six patients to whom weekly paclitaxel and carboplatin were administered as postoperative chemotherapy were included. Six courses in 21-day cycles were defined as complete treatment. As nutritional indicators, body mass index, weight change rate, serum albumin, total lymphocyte count, prognostic nutritional index, and C-reactive protein-to-albumin ratio (CAR) were compared between complete and incomplete treatment groups. Patients were divided into two groups according to CAR. The number of chemotherapy cycles was compared between these two groups. A Cox proportional hazard model was used for covariate adjustment. RESULTS Several indicators differed between complete and incomplete treatment groups, and among the indicators, CAR had the highest discriminatory ability. The number of chemotherapy cycles was shorter in the high CAR group than in the low CAR group. A high CAR was associated with chemotherapy interruption even after adjusting for covariates. CONCLUSION Based on CAR, nutritional status before chemotherapy is suggested to be associated with the risk of chemotherapy discontinuation.
Collapse
Affiliation(s)
- Naoko Nomoto
- Department of Nutrition and Metabolic Medicine, Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba 260-8670, Japan
- Department of Clinical Nutrition, Chiba University Hospital, Chiba 260-8677, Japan
| | - Shinichi Tate
- Division of Gynecology, Chiba University Hospital, Chiba 260-8677, Japan
| | - Makoto Arai
- Department of Medical Oncology, Chiba University Hospital, Chiba 260-8677, Japan
| | - Shinji Iizaka
- School of Nutrition, College of Nursing and Nutrition, Shukutoku University, Chiba 260-8701, Japan
| | - Chisato Mori
- Department of Sustainable Health Science, Center for Preventive Medical Sciences, Chiba University, Chiba 263-8522, Japan
- Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, Chiba 263-8522, Japan
| | - Kenichi Sakurai
- Department of Nutrition and Metabolic Medicine, Center for Preventive Medical Sciences, Chiba University, Chiba 263-8522, Japan
| |
Collapse
|
|
11
|
Zhou B, Shi X, Tang X, Zhao Q, Wang L, Yao F, Hou Y, Wang X, Feng W, Wang L, Sun X, Wang L, Hu S. Functional isolation, culture and cryopreservation of adult human primary cardiomyocytes. Signal Transduct Target Ther 2022; 7:254. [PMID: 35882831 PMCID: PMC9325714 DOI: 10.1038/s41392-022-01044-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/11/2022] [Accepted: 05/26/2022] [Indexed: 12/27/2022] Open
Abstract
Cardiovascular diseases are the most common cause of death globally. Accurately modeling cardiac homeostasis, dysfunction, and drug response lies at the heart of cardiac research. Adult human primary cardiomyocytes (hPCMs) are a promising cellular model, but unstable isolation efficiency and quality, rapid cell death in culture, and unknown response to cryopreservation prevent them from becoming a reliable and flexible in vitro cardiac model. Combing the use of a reversible inhibitor of myosin II ATPase, (-)-blebbistatin (Bleb), and multiple optimization steps of the isolation procedure, we achieved a 2.74-fold increase in cell viability over traditional methods, accompanied by better cellular morphology, minimally perturbed gene expression, intact electrophysiology, and normal neurohormonal signaling. Further optimization of culture conditions established a method that was capable of maintaining optimal cell viability, morphology, and mitochondrial respiration for at least 7 days. Most importantly, we successfully cryopreserved hPCMs, which were structurally, molecularly, and functionally intact after undergoing the freeze-thaw cycle. hPCMs demonstrated greater sensitivity towards a set of cardiotoxic drugs, compared to human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Further dissection of cardiomyocyte drug response at both the population and single-cell transcriptomic level revealed that hPCM responses were more pronouncedly enriched in cardiac function, whereas hiPSC-CMs responses reflected cardiac development. Together, we established a full set of methodologies for the efficient isolation and prolonged maintenance of functional primary adult human cardiomyocytes in vitro, unlocking their potential as a cellular model for cardiovascular research, drug discovery, and safety pharmacology.
Collapse
Affiliation(s)
- Bingying Zhou
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China
| | - Xun Shi
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoli Tang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Quanyi Zhao
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China
| | - Le Wang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fang Yao
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongfeng Hou
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,18 Jinma Industrial Park, Fangshan District, Beijing, China
| | - Xianqiang Wang
- Department of Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Feng
- Department of Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liqing Wang
- Department of Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaogang Sun
- Department of Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Wang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China
| | - Shengshou Hu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. .,Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China. .,Department of Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
12
|
Kim Y, Seidman JG, Seidman CE. Genetics of cancer therapy-associated cardiotoxicity. J Mol Cell Cardiol 2022; 167:85-91. [PMID: 35358500 PMCID: PMC9107514 DOI: 10.1016/j.yjmcc.2022.03.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/12/2022] [Accepted: 03/25/2022] [Indexed: 01/03/2023]
Abstract
As the number of cancer survivors has increased significantly over the last decades due to aging of population and development of effective cancer therapies, side effects from cancer therapies have been increasingly recognized. High-dose anthracyclines, immunotherapies, and concurrent radiation, as well as traditional cardiovascular risk factors such as smoking, hypertension, diabetes, hyperlipidemia, and obesity increase risks for unintended cardiovascular toxicity. However, these factors do not fully explain why only a subset of patients develop adverse cardiovascular sequelae from cancer therapies. Recent studies demonstrate that genetics play a substantial role in susceptibility to development of cardiovascular toxicities from cancer therapies. Common single nucleotide polymorphisms in multiple genes involved in various cellular pathways including membrane transport, stress response, and sarcomeres are recognized to increase risks for these toxicities. Pathogenic variants in the genes encoding proteins that comprise sarcomeres also contribute to cardiomyopathy following cancer therapies. Furthermore, genetic manipulations of model systems indicate mechanisms by which cardiotoxicities emerge following cancer immunomodulatory therapies. Continued efforts are needed to enable insights into cardiovascular responsiveness to these multi-targeted therapies, improve risk stratification of patients, and enable therapeutic interventions that limit these unintended adverse consequences from life-saving cancer treatments.
Collapse
Affiliation(s)
- Yuri Kim
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, United States of America; Department of Genetics, Harvard Medical School, Boston, MA, United States of America.
| | - Jonathan G Seidman
- Department of Genetics, Harvard Medical School, Boston, MA, United States of America
| | - Christine E Seidman
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, United States of America; Department of Genetics, Harvard Medical School, Boston, MA, United States of America; Howard Hughes Medical Institute, Chevy Chase, MD, United States of America
| |
Collapse
|
|
13
|
Herrmann J, Lenihan D, Armenian S, Barac A, Blaes A, Cardinale D, Carver J, Dent S, Ky B, Lyon AR, López-Fernández T, Fradley MG, Ganatra S, Curigliano G, Mitchell JD, Minotti G, Lang NN, Liu JE, Neilan TG, Nohria A, O'Quinn R, Pusic I, Porter C, Reynolds KL, Ruddy KJ, Thavendiranathan P, Valent P. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J 2022; 43:280-299. [PMID: 34904661 PMCID: PMC8803367 DOI: 10.1093/eurheartj/ehab674] [Citation(s) in RCA: 327] [Impact Index Per Article: 109.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/28/2021] [Accepted: 09/10/2021] [Indexed: 12/16/2022] Open
Abstract
The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.
Collapse
Affiliation(s)
- Joerg Herrmann
- Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA
| | - Daniel Lenihan
- International Cardio-Oncology Society, 465 Lucerne Ave., Tampa, FL 33606, USA
| | - Saro Armenian
- City of Hope Comprehensive Cancer Center, Department of Population Sciences, 500 E Duarte Rd, Duarte, CA 91010, USA
| | - Ana Barac
- MedStar Heart and Vascular Institute, Georgetown University, 10 Irving Street Northwest Suite NW, Washington, DC 20010, USA
| | - Anne Blaes
- University of Minnesota, Division of Hematology/Oncology, 420 Delaware Street SE, Minneapolis, MN 55455, USA
| | - Daniela Cardinale
- Cardioncology Unit, European Institute of Oncology, IRCCS, Via Adamello 16, 20139 Milan, Italy
| | - Joseph Carver
- Abraham Cancer Center, University of Pennsylvania, Philadelphia, 3400 Civic Center Boulevard, Pavilion 2nd Floor, Philadelphia, PA 19104, USA
| | - Susan Dent
- Duke Cancer Institute, Department of Medicine, Duke University, 20 Duke Medicine Circle, Durham, NA 27704, USA
| | - Bonnie Ky
- Division of Cardiology, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA
| | - Alexander R Lyon
- Cardio-Oncology Service, Royal Brompton Hospital, Imperial College, Sydney St, London SW3 6NP, United Kingdom
| | - Teresa López-Fernández
- Division of Cardiology; Cardiac Imaging and Cardio-Oncology Unit; La Paz University Hospital, IdiPAZ Research Institute, CIBER CV, C. de Pedro Rico, 6, 28029 Madrid, Spain
| | - Michael G Fradley
- Division of Cardiology, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA
| | - Sarju Ganatra
- Cardio-Oncology Program, Department of Cardiovascular Medicine, Lahey Hospital and Medical Center, 41 Burlington Mall Road, Burlington, MA 01805, USA
| | - Giuseppe Curigliano
- Department of Oncology and Hemato-Oncology, University of Milano, Via Festa del Perdono 7. 20122 Milano, Italy
- European Institute of Oncology, IRCCS, Via Adamello 16, 20139 Milan, Italy
| | - Joshua D Mitchell
- Cardio-Oncology Center of Excellence, Washington University, 4921 Parkview Pl, St. Louis, MO 63110, USA
| | - Giorgio Minotti
- Department of Medicine, University Campus Bio-Medico, Via Álvaro del Portillo, 21, 00128 Roma, Italy
| | - Ninian N Lang
- British Heart Foundation Centre for Cardiovascular Sciences, University of Glasgow, 126 University Place, Glasgow, G12 8TA Scotland, United Kingdom
| | - Jennifer E Liu
- Memorial Sloan Kettering Cancer Center, Department of Medicine/Cardiology Service, 1275 York Ave, New York, NY 10065, USA
| | - Tomas G Neilan
- Cardio-oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA
| | - Anju Nohria
- Cardio-Oncology Program, Brigham and Women’s Hospital and Dana Farber Cancer Institute, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
| | - Rupal O'Quinn
- Division of Cardiology, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA
| | - Iskra Pusic
- Washington University School of Medicine, Division of Oncology, 4921 Parkview Place, St. Louis, MO 63110, USA
| | - Charles Porter
- Cardiovascular Medicine, Cardio-Oncology Unit, University of Kansas Medical Center, 4000 Cambridge Street, Kansas City, KS 66160, USA
| | - Kerry L Reynolds
- Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA
| | - Kathryn J Ruddy
- Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55902, USA
| | - Paaladinesh Thavendiranathan
- Department of Medicine, Division of Cardiology, Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Centre, University Health Network, University of Toronto, 585 University Ave, Toronto, ON M5G 2N2, Canada
| | - Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| |
Collapse
|
|
14
|
Afrin H, Salazar CJ, Kazi M, Ahamad SR, Alharbi M, Nurunnabi M. Methods of screening, monitoring and management of cardiac toxicity induced by chemotherapeutics. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.01.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
|
|
15
|
Viswanathan T, Lang CC, Petty RD, Baxter MA. Cardiotoxicity and Chemotherapy-The Role of Precision Medicine. Diseases 2021; 9:90. [PMID: 34940028 PMCID: PMC8699963 DOI: 10.3390/diseases9040090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/25/2021] [Accepted: 11/28/2021] [Indexed: 11/16/2022] Open
Abstract
Cancer and cardiovascular disease are the leading causes of death in the United Kingdom. Many systemic anticancer treatments are associated with short- and long-term cardiotoxicity. With improving cancer survival and an ageing population, identifying those patients at the greatest risk of cardiotoxicity from their cancer treatment is becoming a research priority and has led to a new subspecialty: cardio-oncology. In this concise review article, we discuss cardiotoxicity and systemic anticancer therapy, with a focus on chemotherapy. We also discuss the challenge of identifying those at risk and the role of precision medicine as we strive for a personalised approach to this clinical scenario.
Collapse
Affiliation(s)
- Thyla Viswanathan
- Dundee School of Medicine, Ninewells Hospital, University of Dundee, Dundee DD2 1SY, UK;
| | - Chim C. Lang
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee DD2 1SY, UK; (C.C.L.); (R.D.P.)
- UKM Medical Molecular Biology Institute (UMBI), Jalan Yaacob Latif, Cheras, Kuala Lumpur 56000, Malaysia
| | - Russell D. Petty
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee DD2 1SY, UK; (C.C.L.); (R.D.P.)
- Tayside Cancer Centre, Ninewells Hospital and Medical School, NHS Tayside, Dundee DD2 1SY, UK
| | - Mark A. Baxter
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee DD2 1SY, UK; (C.C.L.); (R.D.P.)
- Tayside Cancer Centre, Ninewells Hospital and Medical School, NHS Tayside, Dundee DD2 1SY, UK
| |
Collapse
|
|
16
|
Xu Z, Jin Y, Gao Z, Zeng Y, Du J, Yan H, Chen X, Ping L, Lin N, Yang B, He Q, Luo P. Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib. Autophagy 2021; 18:1152-1173. [PMID: 34432562 DOI: 10.1080/15548627.2021.1965712] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Excessive macroautophagy/autophagy is one of the causes of cardiomyocyte death induced by cardiovascular diseases or cancer therapy, yet the underlying mechanism remains unknown. We and other groups previously reported that autophagy might contribute to cardiomyocyte death caused by sunitinib, a tumor angiogenesis inhibitor that is widely used in clinic, which may help to understand the mechanism of autophagy-induced cardiomyocyte death. Here, we found that sunitinib-induced autophagy leads to apoptosis of cardiomyocyte and cardiac dysfunction as the cardiomyocyte-specific Atg7-/+ heterozygous mice are resistant to sunitinib. Sunitinib-induced maladaptive autophagy selectively degrades the cardiomyocyte survival mediator CCN2 (cellular communication network factor 2) through the TOLLIP (toll interacting protein)-mediated endosome-related pathway and cardiomyocyte-specific knockdown of Ccn2 through adeno-associated virus serotype 9 (AAV9) mimics sunitinib-induced cardiac dysfunction in vivo, suggesting that the autophagic degradation of CCN2 is one of the causes of sunitinib-induced cardiotoxicity and death of cardiomyocytes. Remarkably, deletion of Hmgb1 (high mobility group box 1) inhibited sunitinib-induced cardiomyocyte autophagy and apoptosis, and the HMGB1-specific inhibitor glycyrrhizic acid (GA) significantly mitigated sunitinib-induced autophagy, cardiomyocyte death and cardiotoxicity. Our study reveals a novel target protein of autophagic degradation in the regulation of cardiomyocyte death and highlights the pharmacological inhibitor of HMGB1 as an attractive approach for improving the safety of sunitinib-based cancer therapy.
Collapse
Affiliation(s)
- Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China
| | - Ying Jin
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China
| | - Zizheng Gao
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China
| | - Yan Zeng
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China
| | - Jiangxia Du
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China
| | - Xueqin Chen
- Department of Oncology, Hangzhou First People's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R.China
| | - Li Ping
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China
| | - Nengming Lin
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R.China
| | - Bo Yang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China.,Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang, P.R.China.,Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China.,Department of Pharmacology and Toxicology, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| |
Collapse
|
|
17
|
Fiala O, Ostašov P, Rozsypalová A, Hora M, Šorejs O, Šustr J, Bendová B, Trávníček I, Filipovský J, Fínek J, Büchler T. Impact of Concomitant Cardiovascular Medication on Survival of Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib or Pazopanib in the First Line. Target Oncol 2021; 16:643-652. [PMID: 34363554 DOI: 10.1007/s11523-021-00829-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Patients with metastatic renal cell carcinoma (mRCC) are often elderly and have various comorbidities, including cardiovascular diseases. Although these patients have extensive co-exposure to targeted therapy and cardiovascular drugs, the impact of this co-exposure on outcomes for patients with mRCC remains unclear. OBJECTIVE Our objective was to evaluate the association between the use of cardiovascular medication and survival of patients with mRCC. METHODS The study included 343 consecutive patients with mRCC treated with sunitinib or pazopanib in the first line. Clinical data obtained from the Renal Cell Carcinoma Information System (RENIS) clinical registry and hospital information systems were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were compared according to the use of common medications, including antihypertensives (i.e., β-blockers [BBs], angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics), acetylsalicylic acid (aspirin), statins, and proton pump inhibitors. RESULTS The univariate Cox analysis evaluating the impact of the assessed comedications on patient survival revealed that only BBs were significantly associated with PFS (hazard ratio [HR] 0.533, p < 0.001) and OS (HR 0.641, p = 0.006). The median PFS and OS for users of BBs was 18.39 and 37.60 months versus 8.16 and 20.4 months for patients not using BBs (p < 0.001 and p < 0.001, respectively). The Cox multivariate analysis showed that the use of BBs was a significant factor for both PFS (HR 0.428, p = 0.001) and OS (HR 0.518, p = 0.001). CONCLUSIONS The results of this retrospective study suggest that the use of BBs is associated with favorable outcomes for patients with mRCC treated with sunitinib or pazopanib in the first line.
Collapse
Affiliation(s)
- Ondřej Fiala
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Pilsen, Charles University, alej Svobody 80, 304 60, Pilsen, Czech Republic.
- Laboratory of Cancer Treatment and Tissue Regeneration, Faculty of Medicine in Pilsen, Biomedical Center, Charles University, alej Svobody 76, Pilsen, Czech Republic.
| | - Pavel Ostašov
- Laboratory of Tumor Biology and Immunotherapy, Faculty of Medicine in Pilsen, Biomedical Center, Charles University, alej Svobody 76, Pilsen, Czech Republic
| | - Aneta Rozsypalová
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, Prague, Czech Republic
| | - Milan Hora
- Department of Urology, Faculty of Medicine and University Hospital in Pilsen, Charles University, E. Beneše 13, Pilsen, Czech Republic
| | - Ondřej Šorejs
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Pilsen, Charles University, alej Svobody 80, 304 60, Pilsen, Czech Republic
- Laboratory of Cancer Treatment and Tissue Regeneration, Faculty of Medicine in Pilsen, Biomedical Center, Charles University, alej Svobody 76, Pilsen, Czech Republic
| | - Jan Šustr
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Pilsen, Charles University, alej Svobody 80, 304 60, Pilsen, Czech Republic
| | - Barbora Bendová
- Department of Urology, Faculty of Medicine and University Hospital in Pilsen, Charles University, E. Beneše 13, Pilsen, Czech Republic
| | - Ivan Trávníček
- Department of Urology, Faculty of Medicine and University Hospital in Pilsen, Charles University, E. Beneše 13, Pilsen, Czech Republic
| | - Jan Filipovský
- 2nd Department of Internal Medicine, Faculty of Medicine and University Hospital in Pilsen, Charles University, E. Beneše 13, Pilsen, Czech Republic
| | - Jindřich Fínek
- Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Pilsen, Charles University, alej Svobody 80, 304 60, Pilsen, Czech Republic
| | - Tomáš Büchler
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, Prague, Czech Republic
| |
Collapse
|
|
18
|
Cherri M, Ferraro M, Mohammadifar E, Quaas E, Achazi K, Ludwig K, Grötzinger C, Schirner M, Haag R. Biodegradable Dendritic Polyglycerol Sulfate for the Delivery and Tumor Accumulation of Cytostatic Anticancer Drugs. ACS Biomater Sci Eng 2021; 7:2569-2579. [PMID: 34061498 DOI: 10.1021/acsbiomaterials.1c00439] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Targeted delivery and extended blood circulation of anticancer drugs have been the challenges for decreasing the adverse side effects and improving the therapeutic efficiency in cancer chemotherapy. Herein, we present a drug delivery system (DDS) based on biodegradable dendritic polyglycerol sulfate-bearing poly(caprolactone) (dPGS-PCL) chains, which has been synthesized on 20 g scale using a straightforward two-step protocol. In vivo fluorescence imaging demonstrated a significant accumulation of the DDS in the tumor environment. Sunitinib, an anticancer drug, was loaded into the DDS and the drug-induced toxicity was investigated in vitro and in vivo. The drug encapsulated in dPGS-PCL and the free drug showed similar toxicities in A431 and HT-29 cells, and the cellular uptake was comparable. The straightforward and large-scale synthesis, the organic solvent-free drug-loading approach, together with the tumor targetability of the biodegradable dendritic polyglycerols, render this copolymer a promising candidate for targeted cancer nanomedicine drug delivery systems.
Collapse
Affiliation(s)
- Mariam Cherri
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
| | - Magda Ferraro
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
| | - Ehsan Mohammadifar
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
| | - Elisa Quaas
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
| | - Katharina Achazi
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
| | - Kai Ludwig
- Research Center for Electron Microscopy and Core Facility BioSupraMol, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Fabeckstr. 36a, 14195 Berlin, Germany
| | - Carsten Grötzinger
- Department of Hepatology and Gastroenterology, and Molecular Cancer Research Center (MKFZ), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, CVK Augustenburger Platz 1, 13353 Berlin, Germany.,German Cancer Consortium (DKTK), Partner Site Berlin, 13353 Berlin, Germany
| | - Michael Schirner
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
| | - Rainer Haag
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
| |
Collapse
|
|
19
|
Zhang X, Zhang H, Dai J, Liu Z, Zhu X, Ni Y, Yin X, Sun G, Zhu S, Chen J, Zhao J, Wang J, Zeng H, Shen P. The influence of dynamic changes in lipid metabolism on survival outcomes in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. Jpn J Clin Oncol 2021; 50:1454-1463. [PMID: 32719852 DOI: 10.1093/jjco/hyaa120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 07/23/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The role of lipid metabolic status in tyrosine kinase inhibitors-treated patients with metastatic renal cell carcinoma is insufficient. OBJECTIVE To analyse the influence of dynamic changes of lipid metabolism on survival outcomes in tyrosine kinase inhibitors-treated metastatic renal cell carcinoma. PATIENTS AND METHODS Serum levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol were collected, both before tyrosine kinase inhibitors therapy and at different time points of tyrosine kinase inhibitors treatment duration. Other clinicopathological and survival data were retrospectively reviewed. The clinical outcomes, including tumour response, progression-free survival and overall survival, were analysed. Kaplan-Meier survival curves were plotted and the log-rank test was used to analyse statistical significance. RESULTS A total of 127 patients with metastatic renal cell carcinoma, initially treated with tyrosine kinase inhibitors as first-line systemic therapy, were included. In the whole cohort, the serum levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol fluctuated but gradually increased during tyrosine kinase inhibitors treatment. In survival analysis, the higher serum level of lipid metabolism, the longer progression-free survival was observed. In terms of overall survival, all post-treatment lipid metabolism, including the percentages of increasing change, were correlated with better survival. Further multivariate analysis showed that patients with five components of treatment-related dysfunction of lipid metabolism had superior survival to those with less than five components. However, lipid metabolism was not correlated with tumour response. CONCLUSION Increasing parameters of lipid metabolism indicated improvement of survival in tyrosine kinase inhibitors-treated metastatic renal cell carcinoma, especially the increasing percentages.
Collapse
Affiliation(s)
- Xingming Zhang
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Haoran Zhang
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Jindong Dai
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Zhenhua Liu
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Xudong Zhu
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Yuchao Ni
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Xiaoxue Yin
- Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, P.R. China
| | - Guangxi Sun
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Sha Zhu
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Junru Chen
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Jinge Zhao
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Jia Wang
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Hao Zeng
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| | - Pengfei Shen
- Department of Urology, West China Hospital, Sichuan University, Chengdu.,Institute of Urology, West China Hospital, Sichuan University, Chengdu
| |
Collapse
|
|
20
|
Kunimasa K, Oka T, Hara S, Yamada N, Oizumi S, Miyashita Y, Kamada R, Funamoto T, Kawachi H, Kawamura T, Inoue T, Kuhara H, Tamiya M, Nishino K, Matsunaga T, Imamura F, Fujita M, Kumagai T. Osimertinib is associated with reversible and dose-independent cancer therapy-related cardiac dysfunction. Lung Cancer 2020; 153:186-192. [PMID: 33277055 DOI: 10.1016/j.lungcan.2020.10.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/01/2022]
Abstract
INTRODUCTION The use of osimertinib is associated with the risk of cancer therapy-related cardiac dysfunction (CTRCD) for EGFR-mutated non-small cell lung cancer (NSCLC) patients. In this study, we aimed to clarify the clinical features of patients with CTRCD associated with osimertinib. METHODS A total of 183 cases of advanced EGFR-mutated NSCLC who received osimertinib monotherapy from January 2014 to December 2019 were evaluated. Longitudinal changes in LVEF were evaluated in 58 patients by serial echocardiography before and after osimertinib administration. RESULTS Of 58 patients, 16 patients (8.7%) had decreased LVEF of 10 units or more and 8 patients (4.4%) met the CTRCD criteria. Overall, LVEF significantly decreased after osimertinib treatment from a mean value of 69% (range, 52-82%) at baseline to 66% (26-75%) (p < 0.001). During osimertinib treatment, LVEF remained low but did not decline any further. Discontinuation, dose reduction, or switching to another EGFR tyrosine kinase inhibitors resulted in recovery in 6 out of 8 CTRCD patients. Multivariate analysis showed that history of heart disease was a significant predictor of CTRCD (ORR, 4.97; 95% confidence interval [CI], 1.26-19.6; P = 0.022). CONCLUSIONS Osimertinib was associated with the risk of CTRCD, which is dose-independent and reversible with drug withdrawal.
Collapse
Affiliation(s)
- Kei Kunimasa
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
| | - Toru Oka
- Department of Onco-Cardiology, Osaka International Cancer Institute, Osaka, Japan
| | - Satoshi Hara
- Department of Respiratory Medicine, Itami City Hospital, Itami, Japan
| | - Noriyuki Yamada
- Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | - Satoshi Oizumi
- Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Hokkaido, Japan
| | - Yoshihiro Miyashita
- Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan
| | - Risa Kamada
- Department of Onco-Cardiology, Osaka International Cancer Institute, Osaka, Japan
| | - Tomoya Funamoto
- Department of Respiratory Medicine, Itami City Hospital, Itami, Japan
| | - Hayato Kawachi
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Takahisa Kawamura
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Takako Inoue
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Hanako Kuhara
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Motohiro Tamiya
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Kazumi Nishino
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Takashi Matsunaga
- Department of Medical Informatics, Osaka International Cancer Institute, Osaka, Japan
| | - Fumio Imamura
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Masashi Fujita
- Department of Onco-Cardiology, Osaka International Cancer Institute, Osaka, Japan
| | - Toru Kumagai
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
| |
Collapse
|
|
21
|
Comprehensive geriatric assessment is an independent prognostic factor in older patients with metastatic renal cell cancer treated with first-line Sunitinib or Pazopanib: a single center experience. J Geriatr Oncol 2020; 12:290-297. [PMID: 32972885 DOI: 10.1016/j.jgo.2020.09.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/09/2020] [Accepted: 09/02/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND There is poor data on the prognostic role of Comprehensive Geriatric Assessment (CGA) in older patients with metastatic renal cell carcinoma (mRCC) treated with first line Tyrosine Kinase Inhibitors (TKIs). MATERIALS AND METHODS We retrospectively reviewed the clinical charts of mRCC patients older than 70 years treated at our Institute with first-line Sunitinib or Pazopanib for at least 6 months. Every patient received a CGA at baseline and was identified as fit, vulnerable or frail according to Balducci's Criteria. We then assessed the impact of CGA category on survival, disease control and tolerability of TKIs. RESULTS We identified 86 eligible patients. Median age: 74.5 years, 56% males; 45.4% were fit, 37.2% vulnerable and 17.4% frail at CGA. There were no significant differences in the rate of Grade (G)1-2 and G3-4 toxicities, dose reduction rates, PFS and OS between Sunitinib and Pazopanib. Fit, vulnerable and frail patients achieved significantly different median PFS (18.9 vs 11.2 vs 5.1 months; p < 0.001) and OS (35.5 vs 14.6 vs 10.9 months; p < 0.001). Patients categorized as fit had higher chance of receiving a second-line treatment (66.6% vs 28.9% in vulnerable/frail; p = 0.002). The incidence of G3/4 events was significantly lower in the fit subgroup (19% vs 45% in vulnerable/frail; p = 0.0025). CONCLUSIONS In our retrospective single-center experience, CGA could accurately discriminate patients with higher risk of experiencing G3/4 toxicities, shorter PFS, and lower chance of receiving a second line treatment. CGA strongly impacted on OS, independently from International mRCC Database Consortium (IMDC) classification.
Collapse
|
|
22
|
Heraudet L, Domblides C, Daste A, Lefort F, Bernhard JC, Ravaud A, Gross-Goupil M. Safety of sunitinib in patients with renal cell carcinoma following nephrectomy. Expert Opin Drug Saf 2020; 19:799-806. [PMID: 32521179 DOI: 10.1080/14740338.2020.1774551] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION The safety profile characteristics of sunitinib were evaluated in patients who underwent nephrectomy for kidney cancer. AREAS COVERED In this literature review, safety data were evaluated from phase III trials investigating sunitinib following nephrectomy, either in the more recent adjuvant setting after nephrectomy or in the metastatic setting, with a focus on new data from the CARMENA and SURTIME trials. In particular, the aim was to determine the specificity of toxicity in the adjuvant setting. EXPERT OPINION In the adjuvant setting, even if the toxicity profile of sunitinib does not differ significantly from that in the metastatic setting, the importance of the dose intensity and, thus, exposure has been emphasized. Consequently, as described mainly in the metastatic setting, management of the adverse effects of sunitinib remains critical.
Collapse
Affiliation(s)
- Luc Heraudet
- Department of Medical Oncology, Bordeaux University Hospital , Saint-André, France
| | - Charlotte Domblides
- Department of Medical Oncology, Bordeaux University Hospital , Saint-André, France.,University of Bordeaux , Bordeaux, France
| | - Amaury Daste
- Department of Medical Oncology, Bordeaux University Hospital , Saint-André, France
| | - Félix Lefort
- Department of Medical Oncology, Bordeaux University Hospital , Saint-André, France
| | | | - Alain Ravaud
- Department of Medical Oncology, Bordeaux University Hospital , Saint-André, France.,University of Bordeaux , Bordeaux, France
| | - Marine Gross-Goupil
- Department of Medical Oncology, Bordeaux University Hospital , Saint-André, France
| |
Collapse
|
|
23
|
Brown SA, Ray JC, Herrmann J. Precision Cardio-Oncology: a Systems-Based Perspective on Cardiotoxicity of Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors. J Cardiovasc Transl Res 2020; 13:402-416. [PMID: 32253744 PMCID: PMC8855704 DOI: 10.1007/s12265-020-09992-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 03/18/2020] [Indexed: 02/07/2023]
Abstract
Cancer therapies have been evolving from conventional chemotherapeutics to targeted agents. This has fulfilled the hope of greater efficacy but unfortunately not of greater safety. In fact, a broad spectrum of toxicities can be seen with targeted therapies, including cardiovascular toxicities. Among these, cardiomyopathy and heart failure have received greatest attention, given their profound implications for continuation of cancer therapies and cardiovascular morbidity and mortality. Prediction of risk has always posed a challenge and even more so with the newer targeted agents. The merits of accurate risk prediction, however, are very evident, e.g. facilitating treatment decisions even before the first dose is given. This is important for agents with a long half-life and high potential to induced life-threatening cardiac complications, such as myocarditis with immune checkpoint inhibitors. An opportunity to address these needs in the field of cardio-oncology is provided by the expanding repertoire of "-omics" and other tools in precision medicine and their integration in a systems biology approach. This may allow for new insights into patho-mechanisms and the creation of more precise and cost-effective risk prediction tools with the ultimate goals of improved therapy decisions and prevention of cardiovascular complications. Herein, we explore this topic as a future approach to translating the complexity of cardio-oncology to the reality of patient care.
Collapse
Affiliation(s)
- Sherry-Ann Brown
- Department of Cardiovascular Diseases, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
| | - Jordan C Ray
- Department of Cardiovascular Diseases, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA
| | - Joerg Herrmann
- Department of Cardiovascular Diseases, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA.
| |
Collapse
|
|
24
|
Sayed-Ahmed MM, Alrufaiq BI, Alrikabi A, Abdullah ML, Hafez MM, Al-Shabanah OA. Carnitine Supplementation Attenuates Sunitinib-Induced Inhibition of AMP-Activated Protein Kinase Downstream Signals in Cardiac Tissues. Cardiovasc Toxicol 2020; 19:344-356. [PMID: 30644033 PMCID: PMC6647422 DOI: 10.1007/s12012-018-9500-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
This study has been initiated to investigate whether sunitinib (SUN) alters the expression of key genes engaged in mitochondrial transport and oxidation of long chain fatty acids (LCFA), and if so, whether these alterations should be viewed as a mechanism of SUN-induced cardiotoxicity, and to explore the molecular mechanisms whereby carnitine supplementation could attenuate SUN-induced cardiotoxicity. Adult male Wister albino rats were assigned to one of the four treatment groups: Rats in group 1 received no treatment but free access to tap water for 28 days. Rats in group 2 received L-carnitine (200 mg/kg/day) in drinking water for 28 days. Rats in group 3 received SUN (25 mg/kg/day) in drinking water for 28 days. Rats in group 4 received the same doses of L-carnitine and SUN in drinking water for 28 days. Treatment with SUN significantly increased heart weight, cardiac index, and cardiotoxicity enzymatic indices, as well as severe histopathological changes. Moreover, SUN significantly decreased level of adenosine monophosphate-activated protein kinase (AMPKα2), total carnitine, adenosine triphosphate (ATP) and carnitine palmitoyltransferase I (CPT I) expression and significantly increased acetyl-CoA carboxylase-2 (ACC2) expression and malonyl-CoA level in cardiac tissues. Interestingly, carnitine supplementation resulted in a complete reversal of all the biochemical, gene expression and histopathological changes-induced by SUN to the control values. In conclusion, data from this study suggest that SUN inhibits AMPK downstream signaling with the consequent inhibition of mitochondrial transport of LCFA and energy production in cardiac tissues. Carnitine supplementation attenuates SUN-induced cardiotoxicity.
Collapse
Affiliation(s)
- Mohamed M Sayed-Ahmed
- Pharmacology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11796, Egypt
| | - Badr I Alrufaiq
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia
| | - Ammar Alrikabi
- Pathology Department, College of Medicine, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia
| | - Mashan L Abdullah
- King Abdullah International Medical Research Center, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia
| | - Mohamed M Hafez
- Virology and Immunology Units, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11796, Egypt
| | - Othman A Al-Shabanah
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
| |
Collapse
|
|
25
|
Aldemir MN, Simsek M, Kara AV, Ozcicek F, Mammadov R, Yazıcı GN, Sunar M, Coskun R, Gulaboglu M, Suleyman H. The effect of adenosine triphosphate on sunitinib-induced cardiac injury in rats. Hum Exp Toxicol 2020; 39:1046-1053. [PMID: 32131635 DOI: 10.1177/0960327120909874] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In this study, we aimed to show the effect of adenosine 5'-triphosphate (ATP) on sunitinib-induced cardiac injury in rats. The rats (n = 30) were divided equally into three groups as sunitinib group (SG), sunitinib plus ATP group (SAG), and healthy group (HG); 2 mg/kg ATP was injected intraperitoneally (ip) to the SAG group. Same volume normal saline as solvent was administered ip to the other two groups. After 1 h, 25 mg/kg sunitinib was applied orally via catheter to stomach in the SAG and SG groups. This procedure was repeated once daily for 5 weeks. At the end of this period, all animals were sacrificed and their cardiac tissue was removed. Malondialdehyde (MDA), total glutathione (tGSH), tumor necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) levels in rats' cardiac tissues and troponin I (Tp-I) levels in rats' blood samples were evaluated. Histopathological analysis was also performed in cardiac tissues of the animals. MDA, TNF-α, NF-κB, and Tp-I levels were higher in the SG group compared to the SAG and HG groups (p < 0.001). tGSH levels of the SG group were lower than the SAG and HG groups (p < 0.001). The structure and morphology of cardiac muscle fibers and blood vessels were normal in the control group. In the SG group, obvious cardiac muscle tissue damage with dilated myofibers, locally atrophic myofibers, and congested blood vessels were observed. In the SAG group, marked amelioration in these findings was observed. We showed this for the first time that ATP administration exerts a protective effect against cardiac effects of sunitinib.
Collapse
Affiliation(s)
- M N Aldemir
- Department of Medical Oncology, Faculty of Medicine, Yuzuncu Yil University, Van, Turkey
| | - M Simsek
- Department of Medical Oncology, Yozgat City Hospital, Yozgat, Turkey
| | - A V Kara
- Department of Nephrology, Faculty of Medicine, Erzincan University, Erzincan, Turkey
| | - F Ozcicek
- Department of Internal Medicine, Faculty of Medicine, Erzincan University, Erzincan, Turkey
| | - R Mammadov
- Department Pharmacology, Faculty of Medicine, Erzincan University, Erzincan, Turkey
| | - G N Yazıcı
- Department of Histology and Embryology, Faculty of Medicine, Erzincan University, Erzincan, Turkey
| | - M Sunar
- Department of Anatomy, Faculty of Medicine, Erzincan University, Erzincan, Turkey
| | - R Coskun
- Department of Cardiology, Faculty of Medicine, Erzincan University, Erzincan, Turkey
| | - M Gulaboglu
- Department of Biochemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey
| | - H Suleyman
- Department of Pharmacology, Faculty of Medicine, Erzincan University, Erzincan, Turkey
| |
Collapse
|
|
26
|
Cardiovascular toxicities of therapy for genitourinary malignancies. Urol Oncol 2020; 38:121-128. [DOI: 10.1016/j.urolonc.2019.04.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 04/12/2019] [Accepted: 04/30/2019] [Indexed: 11/22/2022]
|
|
27
|
Nair P, Prado M, Perea‐Gil I, Karakikes I. Concise Review: Precision Matchmaking: Induced Pluripotent Stem Cells Meet Cardio-Oncology. Stem Cells Transl Med 2019; 8:758-767. [PMID: 31020786 PMCID: PMC6646696 DOI: 10.1002/sctm.18-0279] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Accepted: 03/12/2019] [Indexed: 12/15/2022] Open
Abstract
As common chemotherapeutic agents are associated with an increased risk of acute and chronic cardiovascular complications, a new clinical discipline, cardio-oncology, has recently emerged. At the same time, the development of preclinical human stem cell-derived cardiovascular models holds promise as a more faithful platform to predict the cardiovascular toxicity of common cancer therapies and advance our understanding of the underlying mechanisms contributing to the cardiotoxicity. In this article, we review the recent advances in preclinical cancer-related cardiotoxicity testing, focusing on new technologies, such as human induced pluripotent stem cell-derived cardiomyocytes and tissue engineering. We further discuss some of the limitations of these technologies and present future directions. Stem Cells Translational Medicine 2019;8:758&767.
Collapse
Affiliation(s)
- Pooja Nair
- Department of Cardiothoracic SurgeryStanford University School of MedicineStanfordCaliforniaUSA
- Cardiovascular InstituteStanford University School of MedicineStanfordCaliforniaUSA
| | - Maricela Prado
- Department of Cardiothoracic SurgeryStanford University School of MedicineStanfordCaliforniaUSA
- Cardiovascular InstituteStanford University School of MedicineStanfordCaliforniaUSA
| | - Isaac Perea‐Gil
- Department of Cardiothoracic SurgeryStanford University School of MedicineStanfordCaliforniaUSA
- Cardiovascular InstituteStanford University School of MedicineStanfordCaliforniaUSA
| | - Ioannis Karakikes
- Department of Cardiothoracic SurgeryStanford University School of MedicineStanfordCaliforniaUSA
- Cardiovascular InstituteStanford University School of MedicineStanfordCaliforniaUSA
| |
Collapse
|
|
28
|
Burke MJ, Walmsley R, Munsey TS, Smith AJ. Receptor tyrosine kinase inhibitors cause dysfunction in adult rat cardiac fibroblasts in vitro. Toxicol In Vitro 2019; 58:178-186. [DOI: 10.1016/j.tiv.2019.03.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 03/20/2019] [Accepted: 03/21/2019] [Indexed: 12/28/2022]
|
|
29
|
Tocchetti CG, Cadeddu C, Di Lisi D, Femminò S, Madonna R, Mele D, Monte I, Novo G, Penna C, Pepe A, Spallarossa P, Varricchi G, Zito C, Pagliaro P, Mercuro G. From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview. Antioxid Redox Signal 2019; 30:2110-2153. [PMID: 28398124 PMCID: PMC6529857 DOI: 10.1089/ars.2016.6930] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Significance: Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Recent Advances: Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. Critical Issues: CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and it is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and it is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity. Future Directions: Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients who are at a high risk of developing chemotherapy-related CTX, and it may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anticancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system.
Collapse
Affiliation(s)
| | - Christian Cadeddu
- 2 Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Daniela Di Lisi
- 3 Biomedical Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - Saveria Femminò
- 4 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Rosalinda Madonna
- 5 Center of Aging Sciences and Translational Medicine - CESI-MeT, "G. d'Annunzio" University, Chieti, Italy.,6 Department of Internal Medicine, The Texas Heart Institute and Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Donato Mele
- 7 Cardiology Unit, Emergency Department, University Hospital of Ferrara, Ferrara, Italy
| | - Ines Monte
- 8 Department of General Surgery and Medical-Surgery Specialities, University of Catania, Catania, Italy
| | - Giuseppina Novo
- 3 Biomedical Department of Internal Medicine, University of Palermo, Palermo, Italy
| | - Claudia Penna
- 4 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Alessia Pepe
- 9 U.O.C. Magnetic Resonance Imaging, Fondazione Toscana G. Monasterio C.N.R., Pisa, Italy
| | - Paolo Spallarossa
- 10 Clinic of Cardiovascular Diseases, IRCCS San Martino IST, Genova, Italy
| | - Gilda Varricchi
- 1 Department of Translational Medical Sciences, Federico II University, Naples, Italy.,11 Center for Basic and Clinical Immunology Research (CISI) - Federico II University, Naples, Italy
| | - Concetta Zito
- 12 Division of Cardiology, Clinical and Experimental Department of Medicine and Pharmacology, Policlinico "G. Martino" University of Messina, Messina, Italy
| | - Pasquale Pagliaro
- 4 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Giuseppe Mercuro
- 2 Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| |
Collapse
|
|
30
|
Li C, Zou R, Zhang H, Wang Y, Qiu B, Qiu S, Wang W, Xu Y. Upregulation of phosphoinositide 3-kinase prevents sunitinib-induced cardiotoxicity in vitro and in vivo. Arch Toxicol 2019; 93:1697-1712. [DOI: 10.1007/s00204-019-02448-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 04/09/2019] [Indexed: 12/20/2022]
|
|
31
|
Pucci G, Milan A, Paini A, Salvetti M, Cerasari A, Vaudo G. Acute blood pressure elevation associated with biological therapies for cancer: a focus on VEGF signaling pathway inhibitors. Expert Opin Biol Ther 2019; 19:433-442. [PMID: 30888868 DOI: 10.1080/14712598.2019.1594770] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Treatment with biological agents interfering with mechanisms of angiogenesis, such as vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors, was associated with an enhanced risk of acute and severe blood pressure (BP) increase and development of hypertensive emergencies. Areas covered: The present article will review the scientific literature reporting hypertensive emergencies as a complication of biological treatment with VSP inhibitors. Hypertensive emergency is a life-threatening condition characterized by very high BP values (>180/110 mmHg) associated with acute organ damage. The exact mechanism of action is still incompletely clarified. Endothelial dysfunction following reduced bioavailability of nitric oxide has been hypothesized to play an important role in promoting hypertension and the occurrence of acute organ damage. Expert opinion: Prevention, prompt recognition and treatment of hypertensive emergencies associated with treatment with VSP-inhibitors are essential to reduce the risk of adverse events. Not infrequently, the occurrence of hypertensive emergency led to VSP treatment discontinuation, with potential negative consequences on patient overall survival. The present review aims at providing detailed knowledge for the clinician regarding this specific issue, which could be of high impact in usual clinical practice, given the increasing burden of indications to treatment with biological agents targeted to the VEGF pathway.
Collapse
Affiliation(s)
- Giacomo Pucci
- a Department of Medicine , University of Perugia , Perugia , Italy.,b Unit of Internal Medicine , Terni University Hospital , Terni , Italy
| | - Alberto Milan
- c Department of Medical Sciences - Hypertension Center , University of Torino - AOU Città della Salute e della Scienza di Torino , Torino , Italy
| | - Anna Paini
- d Department of Clinical and Experimental Sciences , University of Brescia , Brescia , Italy
| | - Massimo Salvetti
- d Department of Clinical and Experimental Sciences , University of Brescia , Brescia , Italy
| | - Alberto Cerasari
- a Department of Medicine , University of Perugia , Perugia , Italy.,b Unit of Internal Medicine , Terni University Hospital , Terni , Italy
| | - Gaetano Vaudo
- a Department of Medicine , University of Perugia , Perugia , Italy.,b Unit of Internal Medicine , Terni University Hospital , Terni , Italy
| |
Collapse
|
|
32
|
Guha A, Armanious M, Fradley MG. Update on cardio-oncology: Novel cancer therapeutics and associated cardiotoxicities. Trends Cardiovasc Med 2019; 29:29-39. [DOI: 10.1016/j.tcm.2018.06.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/22/2018] [Accepted: 06/03/2018] [Indexed: 02/08/2023]
|
|
33
|
Roles of pharmacogenomics in non-anthracycline antineoplastic-induced cardiovascular toxicities: A systematic review and meta-analysis of genotypes effect. Int J Cardiol 2018; 280:190-197. [PMID: 30594345 DOI: 10.1016/j.ijcard.2018.12.049] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 12/02/2018] [Accepted: 12/17/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND Exploration on genetic roles in antineoplastic-related cardiovascular toxicity has increased with the advancement of genotyping technology. However, knowledge on the extent of genetic determinants in affecting the susceptibility to the cardiovascular toxicities of antineoplastic is limited. This study aims to identify potential single nucleotide polymorphism (SNP) in predicting non-anthracycline antineoplastic-related cardiovascular toxicity. METHODS We systematically searched for original research in PubMed, Cochrane Central Register of Controlled Studies, CINAHL Plus, EMBASE and HuGE Navigator from database inception until January 2018. Studies on association between polymorphism and antineoplastic-induced cardiovascular toxicity in patients treated for cancer of all antineoplastic agents were included except for anthracycline. Case reports, conference abstracts, reviews and non-patient studies were excluded. Data extracted by two independent reviewers were combined with random-effects model and reported according to PRISMA and MOOSE guidelines. RESULTS The 35 studies included examined a total of 219 SNPs in 80 genes, 11 antineoplastic and 5 types of cardiovascular toxicities. Meta-analyses showed that human epidermal growth factor receptor 2 (HER2) rs1136201, a risk variants (pooled OR: 2.43; 1.17-5.06, p = 0.018) is a potential predictors for trastuzumab-related cardiotoxicity. Gene dose effect analysis showed number of variant allele may contribute to the risk too. CONCLUSIONS This review found that HER2 rs1136201 can have the potential in predicting trastuzumab-related heart failure. As such, further studies are needed to confirm the validity of these results as well as determine the economic aspect of using SNPs prior to its implementation as a clinical practice.
Collapse
|
|
34
|
Li J, Wang M, Zhang B, Wu X, Lin TL, Liu XF, Zhou Y, Zhang XH, Xu H, Shen LJ, Zou J, Lu P, Zhang D, Gu WJ, Zhang MX, Pan J, Cao H, Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association. Chinese consensus on management of tyrosine kinase inhibitor-associated side effects in gastrointestinal stromal tumors. World J Gastroenterol 2018; 24:5189-5202. [PMID: 30581268 PMCID: PMC6295840 DOI: 10.3748/wjg.v24.i46.5189] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/04/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have improved the overall survival of patients with gastrointestinal stromal tumors (GISTs), but their side effects can impact dose intensity and, consequently, the clinical benefit. To date, no guideline or consensus has been published on the TKI-associated adverse reactions. Therefore, the Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association organized an expert panel discussion involving representatives from gastrointestinal surgery, medical oncology, cardiology, dermatology, nephrology, endocrinology, and ophthalmology to consider the systemic clinical symptoms, molecular and cellular mechanisms, and treatment recommendations of GISTs. Here, we present the resultant evidence- and experience-based consensus to guide the management of TKI-associated side events in clinical practice.
Collapse
Affiliation(s)
- Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Ming Wang
- Department of Gastrointestinal Surgery, Reiji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Bo Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wu
- Department of General Surgery, the General Hospital of the People’s Liberation Army, Beijing 100853, China
| | - Tian-Long Lin
- Department of Gastrointestinal Surgery, Reiji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Xiu-Feng Liu
- Department of Oncology, The Chinese People’s Liberation Army 81st Hospital, Nanjing 210031, Jiangsu Province, China
| | - Ye Zhou
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Xin-Hua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 320100, Jiangsu Province, China
| | - Li-Jing Shen
- Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
| | - Jing Zou
- Department of Respirology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
| | - Ping Lu
- Department of Dermatology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
| | - Dong Zhang
- Department of Nephrology, The General Hospital of the People’s Liberation Army, Beijing 100853, China
| | - Wei-Jun Gu
- Department of Endocrinology, The General Hospital of the People’s Liberation Army, Beijing 100853, China
| | - Mei-Xia Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian Pan
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hui Cao
- Department of Gastrointestinal Surgery, Reiji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | | |
Collapse
|
|
35
|
Nhola LF, Abdelmoneim SS, Villarraga HR, Kohli M, Grothey A, Bordun KA, Cheung M, Best R, Cheung D, Huang R, Barros-Gomes S, Pitz M, Singal PK, Jassal DS, Mulvagh SL. Echocardiographic Assessment for the Detection of Cardiotoxicity Due to Vascular Endothelial Growth Factor Inhibitor Therapy in Metastatic Renal Cell and Colorectal Cancers. J Am Soc Echocardiogr 2018; 32:267-276. [PMID: 30459123 DOI: 10.1016/j.echo.2018.09.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cardio-oncology is a recently established discipline that focuses on the management of patients with cancer who are at risk for developing cardiovascular complications as a result of their underlying oncologic treatment. In metastatic colorectal cancer (mCRC) and metastatic renal cell carcinoma (mRCC), vascular endothelial growth factor inhibitor (VEGF-i) therapy is commonly used to improve overall survival. Although these novel anticancer drugs may lead to the development of cardiotoxicity, whether early detection of cardiac dysfunction using serial echocardiography could potentially prevent the development of heart failure in this patient population requires further study. The aim of this study was to investigate the role of two-dimensional speckle-tracking echocardiography in the detection of cardiotoxicity due to VEGF-i therapy in patients with mCRC or mRCC. METHODS Patients with mRCC or mCRC were evaluated using serial echocardiography at baseline and 1, 3, and 6 months following VEGF-i treatment. RESULTS A total of 40 patients (34 men; mean age, 63 ± 9 years) receiving VEGF-i therapy were prospectively recruited at two academic centers: 26 (65%) were receiving sunitinib, eight (20%) pazopanib, and six (15%) bevacizumab. The following observations were made: (1) 8% of patients developed clinically asymptomatic cancer therapeutics-related cardiac dysfunction; (2) 30% of patients developed clinically significant decreases in global longitudinal strain, a marker for early subclinical cardiac dysfunction; (3) baseline abnormalities in global longitudinal strain may identify a subset of patients at higher risk for developing cancer therapeutics-related cardiac dysfunction; and (4) new or worsening hypertension was the most common adverse cardiovascular event, afflicting nearly one third of the study population. CONCLUSIONS Cardiac dysfunction defined by serial changes in myocardial strain assessed using two-dimensional speckle-tracking echocardiography occurs in patients undergoing treatment with VEGF-i for mCRC or mRCC, which may provide an opportunity for preventive interventions.
Collapse
Affiliation(s)
- Lara F Nhola
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Sahar S Abdelmoneim
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota; Division of Cardiology, Orman Heart Center, Assiut University, Assiut, Egypt
| | | | - Manish Kohli
- Department of Oncology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Axel Grothey
- Department of Oncology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Kimberly-Ann Bordun
- Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Matthew Cheung
- Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ryan Best
- Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - David Cheung
- Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Runqing Huang
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Marshall Pitz
- Section of Hematology/Oncology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Pawan K Singal
- Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Davinder S Jassal
- Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Hematology/Oncology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Sharon L Mulvagh
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota; Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
| |
Collapse
|
|
36
|
Ageing alters the severity of Sunitinib-induced cardiotoxicity: Investigating the mitogen activated kinase kinase 7 pathway association. Toxicology 2018; 411:49-59. [PMID: 30393206 DOI: 10.1016/j.tox.2018.10.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 09/28/2018] [Accepted: 10/24/2018] [Indexed: 02/07/2023]
Abstract
Anti-cancer drug Sunitinib is linked to adverse cardiovascular events, which have shown to involve mitogen activated kinase kinase 7 (MKK7) pathway. Sunitinib-induced cardiotoxicity in 3, 12 and 24 months old male Sprague-Dawley rats and MKK7 expression and activation was investigated using the Langendorff perfused heart model followed by Western blot analysis. Cardiac function and infarct size were measured during/after 125 min of Sunitinib treatment. Left ventricular cardiac samples were analysed by qRT-PCR for expression of MKK7 mRNA and cardiac injury associated microRNAs. Infarct size was increased in all Sunitinib treated age groups. Haemodynamic alterations were observed following Sunitinib administration. Left ventricular developed pressure (LVDP) was decreased in all age groups, while heart rate (HR) was decreased in 3 and 12 months groups. Sunitinib treatment decreased the expression of miR-27a in all age groups, while miR-133a and miR-133b levels were increased in 3 months and decreased in 24 months groups. MKK7 mRNA and p-MKK7 levels were decreased in the 3 months group after Sunitinib treatment. MKK7 mRNA level was increased in 24 months group and p-MKK7 levels were increased in 12 months group following Sunitinib treatment. This study highlights the importance and impact of ageing and anti-cancer therapy-induced cardiotoxicity.
Collapse
|
|
37
|
Silva JMD, Lima BDS, Araújo TLD, Lima FET, Cunha GHD. Cardiovascular adverse events associated with oral antineoplastic therapy. Rev Bras Enferm 2018; 71:2561-2569. [PMID: 30304190 DOI: 10.1590/0034-7167-2017-0450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 10/18/2017] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To identify in the literature the cardiovascular adverse events resulting from oral antineoplastic therapy. METHOD Integrative review of the literature through the SCOPUS, Scientific Electronic Library Online (SciELO), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medical Literature Analysis and Retrieval System Online (MEDLINE) databases. The antineoplastic, cardiotoxicity, cardiovascular system and adverse reaction descriptors were used in Portuguese, English and Spanish. We selected 23 articles published between 1985 and 2015. RESULTS Twenty studies were related to cardiac events and eleven to peripheral vascular events. The most frequent adverse cardiac events were reduced left ventricular ejection fraction, myocardial infarction, changes in the electrocardiogram, heart failure and angina, whereas peripheral vascular events were hypertension and thromboembolism. CONCLUSION Oral antineoplastic therapy is associated with different adverse events, including cardiac and peripheral vascular events.
Collapse
Affiliation(s)
- Jacqueline Mota da Silva
- Universidade Federal do Ceará, Faculty of Pharmacy, Dentistry and Nursing, Department of Nursing. Fortaleza, Ceará, Brazil
| | - Beatriz da Silva Lima
- Universidade Federal do Ceará, Faculty of Pharmacy, Dentistry and Nursing, Department of Nursing. Fortaleza, Ceará, Brazil
| | - Thelma Leite de Araújo
- Universidade Federal do Ceará, Faculty of Pharmacy, Dentistry and Nursing, Department of Nursing. Fortaleza, Ceará, Brazil
| | | | - Gilmara Holanda da Cunha
- Universidade Federal do Ceará, Faculty of Pharmacy, Dentistry and Nursing, Department of Nursing. Fortaleza, Ceará, Brazil
| |
Collapse
|
|
38
|
Zhao D, Hou H, Zhang X. Progress in the treatment of solid tumors with apatinib: a systematic review. Onco Targets Ther 2018; 11:4137-4147. [PMID: 30050305 PMCID: PMC6056166 DOI: 10.2147/ott.s172305] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
With the investigation of molecular targets, many agents, such as trastuzumab and ramucirumab, have attained a positive outcome in oncotherapy. Vascular endothelial growth factor (VEGF) is considered a potent factor in angiogenesis and plays an important role in the growth of tumors. Moreover, both VEGF and its receptor are usually excessively expressed in solid tumors and could be hopeful targets for the treatment of neoplasms. Apatinib (YN968D1) is an oral small-molecule tyrosine kinase inhibitor of VEGFR-2. By inhibiting several signaling transduction pathways, it restrains angiogenesis and subsequently controls tumorigenesis. According to current studies, apatinib shows promising application in various solid tumors as a post-second- and post-third-line treatment. It could significantly improve the median overall survival and progression-free survival of patients with tolerated adverse reactions. This paper aims to summarize the recent research on apatinib including the mechanism, pharmacokinetics, trials, adverse reactions, and prospect as a treatment.
Collapse
Affiliation(s)
- Deze Zhao
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China,
| | - Helei Hou
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China,
| | - Xiaochun Zhang
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266003, China,
| |
Collapse
|
|
39
|
Touyz RM, Herrmann J. Cardiotoxicity with vascular endothelial growth factor inhibitor therapy. NPJ Precis Oncol 2018; 2:13. [PMID: 30202791 PMCID: PMC5988734 DOI: 10.1038/s41698-018-0056-z] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/14/2022] Open
Abstract
Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway (VSP) have been important additions in the therapy of various cancers, especially renal cell carcinoma and colorectal cancer. Bevazicumab, the first VSP to receive FDA approval in 2004 targeting all circulating isoforms of VEGF-A, has become one of the best-selling drugs of all times. The second wave of tyrosine kinase inhibitors (TKIs), which target the intracellular site of VEGF receptor kinases, began with the approval of sorafenib in 2005 and sunitinib in 2006. Heart failure was subsequently noted, in 2-4% of patients on bevacizumab and in 3-8% of patients on VSP-TKIs. The very fact that the single-targeted monoclonal antibody bevacizumab can induce cardiotoxicity supports a pathomechanistic role for the VSP and the postulate of the "vascular" nature of VSP inhibitor cardiotoxicity. In this review we will outline this scenario in greater detail, reflecting on hypertension and coronary artery disease as risk factors for VSP inhibitor cardiotoxicity, but also similarities with peripartum and diabetic cardiomyopathy. This leads to the concept that any preexisting or coexisting condition that reduces the vascular reserve or utilizes the vascular reserve for compensatory purposes may pose a risk factor for cardiotoxicity with VSP inhibitors. These conditions need to be carefully considered in cancer patients who are to undergo VSP inhibitor therapy. Such vigilance is not to exclude patients from such prognostically extremely important therapy but to understand the continuum and to recognize and react to any cardiotoxicity dynamics early on for superior overall outcomes.
Collapse
Affiliation(s)
- Rhian M. Touyz
- Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Joerg Herrmann
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN USA
| |
Collapse
|
|
40
|
Zebrafish heart failure models: opportunities and challenges. Amino Acids 2018; 50:787-798. [DOI: 10.1007/s00726-018-2578-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 04/24/2018] [Indexed: 01/03/2023]
|
|
41
|
Noh H, Jung SY, Kwak J, Kim S, Oh SJ, Zang DY, Lee S, Park HL, Jo DJ, Shin JS, Do YR, Kim D, Lee JI. Determination of a radotinib dosage regimen based on dose-response relationships for the treatment of newly diagnosed patients with chronic myeloid leukemia. Cancer Med 2018; 7:1766-1773. [PMID: 29577681 PMCID: PMC5943471 DOI: 10.1002/cam4.1436] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 02/13/2018] [Accepted: 02/17/2018] [Indexed: 01/14/2023] Open
Abstract
Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). Here, using the data from a Phase 3 study conducted in patients with newly diagnosed CP-CML, the dose-efficacy as well as dose-safety relationship analyses were performed to determine a safe and effective initial dosage regimen of radotinib. A significant positive association was detected between the starting dose of radotinib adjusted for body weight (Dose/BW) and the probability of dose-limiting toxicity (≥grade 3 hematologic and nonhematologic toxicity) (P = 0.003). In contrast, a significant inverse association was discovered between Dose/BW and the probability of major molecular response (BCR-ABL1/ABL1 ≤ 0.1%) when controlled for sex (P = 0.033). Moreover, frequent dose interruptions and reductions secondary to radotinib toxicities occurred in the Phase 3 study, resulting in nearly half (44%) of patients receiving a reduced dose at a 12-month follow-up. In conclusion, the results of this study demonstrate the need for initial radotinib dose attenuation to improve the long-term efficacy and safety of radotinib. Hence, the authors suggest a new upfront radotinib dose of 400 mg once daily be tested in patients with newly diagnosed CP-CML.
Collapse
MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Benzamides/administration & dosage
- Benzamides/adverse effects
- Dose-Response Relationship, Drug
- Drug Dosage Calculations
- Female
- Fusion Proteins, bcr-abl/genetics
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Male
- Middle Aged
- Molecular Weight
- Pyrazines/administration & dosage
- Pyrazines/adverse effects
- Treatment Outcome
- Young Adult
Collapse
Affiliation(s)
- Hayeon Noh
- Department of PharmacyCollege of PharmacyYonsei UniversityIncheonKorea
| | - Su Young Jung
- Department of PharmacyCollege of PharmacySeoul National UniversitySeoulKorea
- Research Institute of Pharmaceutical SciencesSeoul National UniversitySeoulKorea
| | - Jae‐Yong Kwak
- Chonbuk National University Medical School & HospitalJeonjuKorea
| | - Sung‐Hyun Kim
- Department of Internal MedicineDong‐A University College of MedicineBusanKorea
| | - Suk Joong Oh
- Department of Internal MedicineKangbuk Samsung HospitalSungkyunkwan University School of MedicineSeoulKorea
| | - Dae Young Zang
- Department of Internal MedicineHallym University Sacred Heart HospitalAnyangKorea
| | - Suhyun Lee
- Department of PharmacyCollege of PharmacySeoul National UniversitySeoulKorea
- Research Institute of Pharmaceutical SciencesSeoul National UniversitySeoulKorea
| | - Hye Lin Park
- Central Research InstituteIL‐YANG Pharmaceutical Co., Ltd.YonginKorea
| | - Dae Jin Jo
- Central Research InstituteIL‐YANG Pharmaceutical Co., Ltd.YonginKorea
| | - Jae Soo Shin
- Central Research InstituteIL‐YANG Pharmaceutical Co., Ltd.YonginKorea
| | - Young Rok Do
- Department of MedicineDongsan Medical CenterKeimyung UniversityDaeguKorea
| | - Dong‐Wook Kim
- Seoul St. Mary's HospitalLeukemia Research InstituteThe Catholic University of KoreaSeoulKorea
| | - Jangik I. Lee
- Department of PharmacyCollege of PharmacySeoul National UniversitySeoulKorea
- Research Institute of Pharmaceutical SciencesSeoul National UniversitySeoulKorea
| |
Collapse
|
|
42
|
|
|
43
|
Truitt R, Mu A, Corbin EA, Vite A, Brandimarto J, Ky B, Margulies KB. Increased Afterload Augments Sunitinib-Induced Cardiotoxicity in an Engineered Cardiac Microtissue Model. JACC Basic Transl Sci 2018; 3:265-276. [PMID: 30062212 PMCID: PMC6059907 DOI: 10.1016/j.jacbts.2017.12.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 12/22/2017] [Accepted: 12/22/2017] [Indexed: 12/17/2022]
Abstract
Sunitinib, a multitargeted oral tyrosine kinase inhibitor, used widely to treat solid tumors, results in hypertension in up to 47% and left ventricular dysfunction in up to 19% of treated individuals. The relative contribution of afterload toward inducing cardiac dysfunction with sunitinib treatment remains unknown. We created a preclinical model of sunitinib cardiotoxicity using engineered microtissues that exhibited cardiomyocyte death, decreases in force generation, and spontaneous beating at clinically relevant doses. Simulated increases in afterload augmented sunitinib cardiotoxicity in both rat and human microtissues, which suggest that antihypertensive therapy may be a strategy to prevent left ventricular dysfunction in patients treated with sunitinib.
Collapse
Key Words
- 2D, 2-dimensional
- 3D, 3-dimensional
- AICAR, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside
- AMPK, adenosine monophosphate-activated protein kinase
- ATP, adenosine triphosphate
- CCCP, carbonyl cyanide m-chlorophenyl hydrazine
- CMT, cardiac microtissue
- DMSO, dimethyl sulfoxide
- EDTA, ethylenediamine tetraacetic acid
- Hu-iPS-CM, human induced pluripotent stem cell cardiomyocyte
- LV, left ventricle
- NRVM, neonatal rat ventricular myocyte
- PDMS, polydimethylsiloxane
- RPMI, Roswell Park Memorial Institute medium
- TMRM, tetramethylrhodamine
- afterload
- apoptosis
- cardiotoxicity
- huMSC, human mesenchymal stem cell
- iPS-CM, induced pluripotent stem cell-derived cardiomyocyte
- sunitinib
- tissue engineering
- toxicology
- tyrosine kinase inhibitors
Collapse
Affiliation(s)
- Rachel Truitt
- Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Anbin Mu
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Elise A. Corbin
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Mechanical Engineering and Applied Mechanics, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Alexia Vite
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jeffrey Brandimarto
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Bonnie Ky
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kenneth B. Margulies
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| |
Collapse
|
|
44
|
Conant G, Lai BFL, Lu RXZ, Korolj A, Wang EY, Radisic M. High-Content Assessment of Cardiac Function Using Heart-on-a-Chip Devices as Drug Screening Model. Stem Cell Rev Rep 2018; 13:335-346. [PMID: 28429185 DOI: 10.1007/s12015-017-9736-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Drug discovery and development continues to be a challenge to the pharmaceutical industry despite great advances in cell and molecular biology that allow for the design of better targeted therapeutics. Many potential drug compounds fail during the clinical trial due to inefficacy and toxicity that were not predicted during preclinical stages. The fundamental problem lies with the use of traditional drug screening models that still largely rely on the use of cell lines or animal cell monolayers, which leads to lack of predictive power of human tissue and organ response to the drug candidates. More physiologically relevant systems are therefore critical in relieving the burden of high failure rates. Emerging knowledge and techniques in tissue engineering and microfabrication have enabled the development of micro-engineered systems - collectively known as organs-on-chips - that may lead to a paradigm shift in preclinical drug screening assays. In this review we explore the technological advances and challenges in the development of heart-on-a-chip models, by addressing current assessment methods for drug-induced cardiotoxicity and providing a perspective on the modifications that should be implemented to realize the full potential of this system.
Collapse
Affiliation(s)
- Genevieve Conant
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
| | - Benjamin Fook Lun Lai
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Rick Xing Ze Lu
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Anastasia Korolj
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
| | - Erika Yan Wang
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Milica Radisic
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada.
- Toronto General Research Institute, Toronto, ON, Canada.
| |
Collapse
|
|
45
|
Varricchi G, Ameri P, Cadeddu C, Ghigo A, Madonna R, Marone G, Mercurio V, Monte I, Novo G, Parrella P, Pirozzi F, Pecoraro A, Spallarossa P, Zito C, Mercuro G, Pagliaro P, Tocchetti CG. Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective. Front Physiol 2018; 9:167. [PMID: 29563880 PMCID: PMC5846016 DOI: 10.3389/fphys.2018.00167] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 02/20/2018] [Indexed: 12/28/2022] Open
Abstract
Antineoplastic drugs can be associated with several side effects, including cardiovascular toxicity (CTX). Biochemical studies have identified multiple mechanisms of CTX. Chemoterapeutic agents can alter redox homeostasis by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species RNS. Cellular sources of ROS/RNS are cardiomyocytes, endothelial cells, stromal and inflammatory cells in the heart. Mitochondria, peroxisomes and other subcellular components are central hubs that control redox homeostasis. Mitochondria are central targets for antineoplastic drug-induced CTX. Understanding the mechanisms of CTX is fundamental for effective cardioprotection, without compromising the efficacy of anticancer treatments. Type 1 CTX is associated with irreversible cardiac cell injury and is typically caused by anthracyclines and conventional chemotherapeutic agents. Type 2 CTX, associated with reversible myocardial dysfunction, is generally caused by biologicals and targeted drugs. Although oxidative/nitrosative reactions play a central role in CTX caused by different antineoplastic drugs, additional mechanisms involving directly and indirectly cardiomyocytes and inflammatory cells play a role in cardiovascular toxicities. Identification of cardiologic risk factors and an integrated approach using molecular, imaging, and clinical data may allow the selection of patients at risk of developing chemotherapy-related CTX. Although the last decade has witnessed intense research related to the molecular and biochemical mechanisms of CTX of antineoplastic drugs, experimental and clinical studies are urgently needed to balance safety and efficacy of novel cancer therapies.
Collapse
Affiliation(s)
- Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy
| | - Pietro Ameri
- Clinic of Cardiovascular Diseases, IRCCS San Martino IST, Genova, Italy
| | - Christian Cadeddu
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Alessandra Ghigo
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Rosalinda Madonna
- Institute of Cardiology, Center of Excellence on Aging, Università degli Studi “G. d'Annunzio” Chieti – Pescara, Chieti, Italy
- Department of Internal Medicine, Texas Heart Institute and Center for Cardiovascular Biology and Atherosclerosis Research, University of Texas Health Science Center, Houston, TX, United States
| | - Giancarlo Marone
- Section of Hygiene, Department of Public Health, University of Naples Federico II, Naples, Italy
- Monaldi Hospital Pharmacy, Naples, Italy
| | - Valentina Mercurio
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Ines Monte
- Department of General Surgery and Medical-Surgery Specialities, University of Catania, Catania, Italy
| | - Giuseppina Novo
- U.O.C. Magnetic Resonance Imaging, Fondazione Toscana G. Monasterio C.N.R., Pisa, Italy
| | - Paolo Parrella
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Flora Pirozzi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Antonio Pecoraro
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Paolo Spallarossa
- Clinic of Cardiovascular Diseases, IRCCS San Martino IST, Genova, Italy
| | - Concetta Zito
- Division of Clinical and Experimental Cardiology, Department of Medicine and Pharmacology, Policlinico “G. Martino” University of Messina, Messina, Italy
| | - Giuseppe Mercuro
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Carlo G. Tocchetti
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| |
Collapse
|
|
46
|
Catino AB, Hubbard RA, Chirinos JA, Townsend R, Keefe S, Haas NB, Puzanov I, Fang JC, Agarwal N, Hyman D, Smith AM, Gordon M, Plappert T, Englefield V, Narayan V, Ewer S, ElAmm C, Lenihan D, Ky B. Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma. Circ Heart Fail 2018; 11:e004408. [PMID: 29664405 PMCID: PMC6360089 DOI: 10.1161/circheartfailure.117.004408] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 02/08/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood. METHODS AND RESULTS In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e'), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0-17.1; P=0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3-10.0; P<0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid-femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all P<0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time. CONCLUSIONS In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function.
Collapse
Affiliation(s)
- Anna B Catino
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Rebecca A Hubbard
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Julio A Chirinos
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Ray Townsend
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Stephen Keefe
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Naomi B Haas
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Igor Puzanov
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - James C Fang
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Neeraj Agarwal
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - David Hyman
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Amanda M Smith
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Mary Gordon
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Theodore Plappert
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Virginia Englefield
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Vivek Narayan
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Steven Ewer
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Chantal ElAmm
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Daniel Lenihan
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.)
| | - Bonnie Ky
- From the Division of Cardiovascular Medicine (A.B.C., J.C.F.) and Division of Oncology (N.A.), Department of Medicine, University of Utah, Salt Lake City; Department of Biostatistics, Epidemiology and Informatics (R.A.H., B.K.), Division of Cardiology (J.A.C., D.H., A.M.S., T.P., V.E., B.K.), Division of Hematology and Oncology (S.K., N.B.H., V.N.), and Division of Nephrology (R.T.), Department of Medicine, and Abramson Cancer Center (S.K., N.B.H., V.N., B.K.), University of Pennsylvania, Philadelphia; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY (I.P.); Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison (S.E.); Division of Cardiovascular Medicine, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH (C.E.); Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.G.); and Division of Cardiology, Department of Medicine, Washington University in St Louis, MO (D.L.).
| |
Collapse
|
|
47
|
Kværner AS, Minaguchi J, Yamani NE, Henriksen C, Ræder H, Paur I, Henriksen HB, Wiedswang G, Smeland S, Blomhoff R, Collins AR, Bøhn SK. DNA damage in blood cells in relation to chemotherapy and nutritional status in colorectal cancer patients—A pilot study. DNA Repair (Amst) 2018; 63:16-24. [DOI: 10.1016/j.dnarep.2018.01.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 01/10/2018] [Accepted: 01/10/2018] [Indexed: 02/08/2023]
|
|
48
|
Narayan V, Ky B. Common Cardiovascular Complications of Cancer Therapy: Epidemiology, Risk Prediction, and Prevention. Annu Rev Med 2018; 69:97-111. [PMID: 29414258 PMCID: PMC6722326 DOI: 10.1146/annurev-med-041316-090622] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
There is growing awareness of the overlap between oncologic and cardiovascular (CV) diseases, including a wide range of CV effects of anticancer therapies. As novel anticancer therapeutics become available and cancer survival outcomes improve, the CV implications of cancer therapy become increasingly important. In addition to outlining the CV effects of commonly used cancer therapies and their consequences for long-term survivorship, this review highlights the recent efforts to improve the risk prediction and prevention of CV toxicity through the evaluation of sensitive measures for early toxicity detection and the implementation of cardioprotective strategies.
Collapse
Affiliation(s)
- Vivek Narayan
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104;
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Bonnie Ky
- Division of Cardiology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104;
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104
- Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| |
Collapse
|
|
49
|
Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ETH. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 1. J Am Coll Cardiol 2017; 70:2536-2551. [PMID: 29145954 PMCID: PMC5825187 DOI: 10.1016/j.jacc.2017.09.1096] [Citation(s) in RCA: 273] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 09/24/2017] [Accepted: 09/26/2017] [Indexed: 12/27/2022]
Abstract
Modern cancer therapy has successfully cured many cancers and converted a terminal illness into a chronic disease. Because cancer patients often have coexisting heart diseases, expert advice from cardiologists will improve clinical outcome. In addition, cancer therapy can also cause myocardial damage, induce endothelial dysfunction, and alter cardiac conduction. Thus, it is important for practicing cardiologists to be knowledgeable about the diagnosis, prevention, and management of the cardiovascular complications of cancer therapy. In this first part of a 2-part review, we will review cancer therapy-induced cardiomyopathy and ischemia. This review is based on a MEDLINE search of published data, published clinical guidelines, and best practices in major cancer centers. With the number of cancer survivors expanding quickly, the time has come for cardiologists to work closely with cancer specialists to prevent and treat cancer therapy-induced cardiovascular complications.
Collapse
Affiliation(s)
- Hui-Ming Chang
- Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Rohit Moudgil
- Department of Cardiology, University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Tiziano Scarabelli
- Division of Cardiology, Virginia Common Wealth University, Richmond, Virginia
| | - Tochukwu M Okwuosa
- Division of Cardiology, Rush University Medical Center, Chicago, Illinois
| | - Edward T H Yeh
- Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri.
| |
Collapse
|
|
50
|
Awada G, de Azambuja E, Awada A. Pharmacologic measures in the prevention of left ventricular dysfunction associated with molecular-targeted therapies in the treatment of cancer patients. Expert Opin Drug Metab Toxicol 2017; 13:1205-1215. [PMID: 29088977 DOI: 10.1080/17425255.2017.1398733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Left ventricular dysfunction (LVD) is an infrequent but significant side effect of certain molecular-targeted cancer therapies and may lead to treatment modification and impact on disease prognosis. There may be a role for beta blockers (BB), angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) in the prevention of LVD. Areas covered: There are multiple definitions for LVD based on clinical and/or imaging features. Molecular-targeted therapies cause reversible LVD. Therapies with well-reported LVD are inhibitors of human epidermal growth factor 2 (HER2), angiogenesis, Abelson murine leukemia viral oncogene homolog (ABL) and the proteasome. BB, ACEI and ARB seem to have a role in the prevention of LVD associated with anthracyclines. Few trials have investigated the role of BB, ACEI and ARB as primary prevention of LVD in molecular-targeted therapies. Their results are not conclusive but a beneficial role cannot be excluded. Expert opinion: Because of inconclusive data, future interventional studies should not include all treated patients with molecular-targeted therapy, but focus on patients at risk for developing LVD. Another option is to study patients who show early signs of LVD to prevent progression to overt heart failure.
Collapse
Affiliation(s)
- Gil Awada
- a Department of Internal Medicine , Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel , Brussels , Belgium
| | - Evandro de Azambuja
- b Medical Oncology Clinic , Institut Jules Bordet, Université Libre de Bruxelles , Brussels , Belgium
| | - Ahmad Awada
- b Medical Oncology Clinic , Institut Jules Bordet, Université Libre de Bruxelles , Brussels , Belgium
| |
Collapse
|