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Guo Q, Wang X, Zhai Y, Dong Y, He Q. Oxaliplatin activates P53/miR-34a/survivin axis in inhibiting the progression of gastric cancer cells. Immun Inflamm Dis 2024; 12:e70004. [PMID: 39254476 PMCID: PMC11386343 DOI: 10.1002/iid3.70004] [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: 05/09/2023] [Revised: 07/31/2024] [Accepted: 08/08/2024] [Indexed: 09/11/2024] Open
Abstract
INTRODUCTION The purpose of this research was to determine how the P53/microRNA-34a (miR-34a)/survivin pathway contributes to oxaliplatin-induced (L-OHP) cell inhibition in gastric cancer. METHODS The BGC-823 gastric cancer cells were selected, and we examined their viability following treatment with L-OHP at different concentrations and time periods. The expression levels of miR-34a, P53, and survivin in the cells were determined. RESULTS In the 12- and 24-h groups, drug concentration of 15 μg/cm² (p < .005 in both) significantly lowered cell viability. In comparison to the control group, miR-34a mRNA expression, P53 mRNA expression, and protein expression were all significantly greater in the 24-h group (p = .0324, p = .0069, p = .0260, respectively), but survivin mRNA and protein expressions were significantly lower than those in the control group (p = .0338, p = .0032, respectively). There was a significant decrease in gastric cancer cells in the miR-34a overexpression group (p = .0020), a significant increase in P53 mRNA and protein expression compared to the control group (p = .0080, p = .0121, respectively), and a significant decrease in survivin mRNA and protein expression compared to the control group. (p = .0213, p = .0069, respectively). CONCLUSION Oxaliplatin inhibits tumor growth, invasion, and metastasis by upregulating miR-34a, activating the expression of the upstream P53 gene, and driving the downregulation of survivin (P53/miR-34a/survivin axis) in BGC-823 gastric cancer cells.
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Affiliation(s)
- Qiang Guo
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Baotou Medical CollegeBaotouChina
- Department of Gastrointestinal SurgeryQi Lu Hospital of Shandong UniversityJinanChina
| | - Xin‐Yuan Wang
- Department of General SurgeryHeNan RongJun HospitalXinxiangChina
| | - Yan‐Chang Zhai
- Department of Gastrointestinal SurgeryQi Lu Hospital of Shandong UniversityJinanChina
| | - Yong‐Wei Dong
- Department of Gastrointestinal SurgeryQi Lu Hospital of Shandong UniversityJinanChina
| | - Qing‐Si He
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Baotou Medical CollegeBaotouChina
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2
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Saleque N, Vastani N, Gentry C, Andersson DA, Israel MR, Bevan S. Topical Oxaliplatin Produces Gain- and Loss-of-Function in Multiple Classes of Sensory Afferents. THE JOURNAL OF PAIN 2024; 25:88-100. [PMID: 37524219 PMCID: PMC10877073 DOI: 10.1016/j.jpain.2023.07.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/03/2023] [Accepted: 07/26/2023] [Indexed: 08/02/2023]
Abstract
The platinum chemotherapeutic oxaliplatin produces dose-limiting pain, dysesthesia, and cold hypersensitivity in most patients immediately after infusion. An improved understanding of the mechanisms underlying these symptoms is urgently required to facilitate the development of symptomatic or preventative therapies. In this study, we have used skin-saphenous nerve recordings in vitro and behavioral experiments in mice to characterize the direct effects of oxaliplatin on different types of sensory afferent fibers. Our results confirmed that mice injected with oxaliplatin rapidly develop mechanical and cold hypersensitivities. We further noted profound changes to A fiber activity after the application of oxaliplatin to the receptive fields in the skin. Most oxaliplatin-treated Aδ- and rapidly adapting Aβ-units lost mechanical sensitivity, but units that retained responsiveness additionally displayed a novel, aberrant cold sensitivity. Slowly adapting Aβ-units did not display mechanical tachyphylaxis, and a subset of these fibers was sensitized to mechanical and cold stimulation after oxaliplatin treatment. C fiber afferents were less affected by acute applications of oxaliplatin, but a subset gained cold sensitivity. Taken together, our findings suggest that direct effects on peripheral A fibers play a dominant role in the development of acute oxaliplatin-induced cold hypersensitivity, numbness, and dysesthesia. PERSPECTIVE: The chemotherapeutic drug oxaliplatin rapidly gives rise to dose-limiting cold pain and dysesthesia. Here, we have used behavioral and electrophysiological studies of mice to characterize the responsible neurons. We show that oxaliplatin directly confers aberrant cold responsiveness to subsets of A-fibers while silencing other fibers of the same type.
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Affiliation(s)
- Nurjahan Saleque
- King's College London, Wolfson CARD, Institute of Psychiatry, Psychology & Neuroscience, London, UK
| | - Nisha Vastani
- King's College London, Wolfson CARD, Institute of Psychiatry, Psychology & Neuroscience, London, UK
| | - Clive Gentry
- King's College London, Wolfson CARD, Institute of Psychiatry, Psychology & Neuroscience, London, UK
| | - David A Andersson
- King's College London, Wolfson CARD, Institute of Psychiatry, Psychology & Neuroscience, London, UK
| | - Mathilde R Israel
- King's College London, Wolfson CARD, Institute of Psychiatry, Psychology & Neuroscience, London, UK
| | - Stuart Bevan
- King's College London, Wolfson CARD, Institute of Psychiatry, Psychology & Neuroscience, London, UK
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3
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Maslarinou A, Manolopoulos VG, Ragia G. Pharmacogenomic-guided dosing of fluoropyrimidines beyond DPYD: time for a polygenic algorithm? Front Pharmacol 2023; 14:1184523. [PMID: 37256234 PMCID: PMC10226670 DOI: 10.3389/fphar.2023.1184523] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 04/19/2023] [Indexed: 06/01/2023] Open
Abstract
Fluoropyrimidines are chemotherapeutic agents widely used for the treatment of various solid tumors. Commonly prescribed FPs include 5-fluorouracil (5-FU) and its oral prodrugs capecitabine (CAP) and tegafur. Bioconversion of 5-FU prodrugs to 5-FU and subsequent metabolic activation of 5-FU are required for the formation of fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate, the active nucleotides through which 5-FU exerts its antimetabolite actions. A significant proportion of FP-treated patients develop severe or life-threatening, even fatal, toxicity. It is well known that FP-induced toxicity is governed by genetic factors, with dihydropyrimidine dehydrogenase (DPYD), the rate limiting enzyme in 5-FU catabolism, being currently the cornerstone of FP pharmacogenomics. DPYD-based dosing guidelines exist to guide FP chemotherapy suggesting significant dose reductions in DPYD defective patients. Accumulated evidence shows that additional variations in other genes implicated in FP pharmacokinetics and pharmacodynamics increase risk for FP toxicity, therefore taking into account more gene variations in FP dosing guidelines holds promise to improve FP pharmacotherapy. In this review we describe the current knowledge on pharmacogenomics of FP-related genes, beyond DPYD, focusing on FP toxicity risk and genetic effects on FP dose reductions. We propose that in the future, FP dosing guidelines may be expanded to include a broader ethnicity-based genetic panel as well as gene*gene and gender*gene interactions towards safer FP prescription.
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Affiliation(s)
- Anthi Maslarinou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
- Individualised Medicine and Pharmacological Research Solutions Center, Alexandroupolis, Greece
| | - Vangelis G. Manolopoulos
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
- Individualised Medicine and Pharmacological Research Solutions Center, Alexandroupolis, Greece
- Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Georgia Ragia
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
- Individualised Medicine and Pharmacological Research Solutions Center, Alexandroupolis, Greece
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4
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Telisnor G, DeRemer DL, Frimpong E, Agyare E, Allen J, Ricks-Santi L, Han B, George T, Rogers SC. Review of genetic and pharmacogenetic differences in cytotoxic and targeted therapies for pancreatic cancer in African Americans. J Natl Med Assoc 2023; 115:164-174. [PMID: 36801148 PMCID: PMC10639003 DOI: 10.1016/j.jnma.2023.01.008] [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: 10/21/2022] [Revised: 12/16/2022] [Accepted: 01/24/2023] [Indexed: 02/19/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality and the incidence is projected to increase by 2030. Despite recent advances in its treatment, African Americans have a 50-60% higher incidence and 30% higher mortality rate when compared to European Americans possibly resulting from differences in socioeconomic status, access to healthcare, and genetics. Genetics plays a role in cancer predisposition, response to cancer therapeutics (pharmacogenetics), and in tumor behavior, making some genes targets for oncologic therapeutics. We hypothesize that the germline genetic differences in predisposition, drug response, and targeted therapies also impact PDAC disparities. To demonstrate the impact of genetics and pharmacogenetics on PDAC disparities, a review of the literature was performed using PubMed with variations of the following keywords: pharmacogenetics, pancreatic cancer, race, ethnicity, African, Black, toxicity, and the FDA-approved drug names: Fluoropyrimidines, Topoisomerase inhibitors, Gemcitabine, Nab-Paclitaxel, Platinum agents, Pembrolizumab, PARP-inhibitors, and NTRK fusion inhibitors. Our findings suggest that the genetic profiles of African Americans may contribute to disparities related to FDA approved chemotherapeutic response for patients with PDAC. We recommend a strong focus on improving genetic testing and participation in biobank sample donations for African Americans. In this way, we can improve our current understanding of genes that influence drug response for patients with PDAC.
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Affiliation(s)
- Guettchina Telisnor
- College of Pharmacy, CaRE(2) Health Equity Center, University of Florida, Gainesville, FL, USA
| | - David L DeRemer
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Esther Frimpong
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida Agricultural and Mechanical University, Tallahassee, FL, USA
| | - Edward Agyare
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida Agricultural and Mechanical University, Tallahassee, FL, USA
| | - John Allen
- College of Pharmacy, CaRE(2) Health Equity Center, University of Florida, Gainesville, FL, USA
| | - Luisel Ricks-Santi
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Bo Han
- Department of Surgery, College of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Thomas George
- Division of Hematology and Oncology, College of Medicine, University of Florida, 600 SW Archer Road, PO BOX 100278, Gainesville, FL 32610- 0278, USA
| | - Sherise C Rogers
- Division of Hematology and Oncology, College of Medicine, University of Florida, 600 SW Archer Road, PO BOX 100278, Gainesville, FL 32610- 0278, USA.
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5
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Zhao W, Meng H. Effects of genetic polymorphism of drug-metabolizing enzymes on the plasma concentrations of antiepileptic drugs in Chinese population. Bioengineered 2022; 13:7709-7745. [PMID: 35290166 PMCID: PMC9278974 DOI: 10.1080/21655979.2022.2036916] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 11/02/2022] Open
Abstract
As a chronic brain disease, epilepsy affects ~50 million people worldwide. The traditional antiepileptic drugs (AEDs) are widely applied but showing various problems. Although the new AEDs have partially solved the problems of traditional AEDs, the current clinical application of traditional AEDs are not completely replaced by new drugs, particularly due to the large individual differences in drug plasma concentrations and narrow therapeutic windows among patients. Therefore, it is still clinically important to continue to treat patients using traditional AEDs with individualized therapeutic plans. To date, our understanding of the molecular and genetic mechanisms regulating plasma concentrations of AEDs has advanced rapidly, expanding the knowledge on the effects of genetic polymorphisms of genes encoding drug-metabolizing enzymes on the plasma concentrations of AEDs. It is increasingly imperative to summarize and conceptualize the clinical significance of recent studies on individualized therapeutic regimens. In this review, we extensively summarize the critical effects of genetic polymorphisms of genes encoding drug-metabolizing enzymes on the plasma concentrations of several commonly used AEDs as well as the clinical significance of testing genotypes related to drug metabolism on individualized drug dosage. Our review provides solid experimental evidence and clinical guidance for the therapeutic applications of these AEDs.
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Affiliation(s)
- Weixuan Zhao
- Department of Neurology, the First Hospital of Jilin University, Jilin University, Changchun, China
| | - Hongmei Meng
- Department of Neurology, the First Hospital of Jilin University, Jilin University, Changchun, China
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6
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Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance. Nat Biomed Eng 2021; 5:1048-1058. [PMID: 34045730 PMCID: PMC8497438 DOI: 10.1038/s41551-021-00728-7] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 04/12/2021] [Indexed: 02/01/2023]
Abstract
In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug. Our findings suggest that the combination of anticancer drugs with distinct mechanisms of action with selective drug release and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.
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7
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Tang M, He B, Zhai J, Wang L. Oral Chinese Patent Medicine Combined With Oxaliplatin-Based Chemotherapy Regimen for the Treatment of Colorectal Cancer: A Network Meta-Analysis. Integr Cancer Ther 2021; 20:15347354211058169. [PMID: 34844475 PMCID: PMC8647226 DOI: 10.1177/15347354211058169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/11/2021] [Accepted: 10/20/2021] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVE To access the comparative effectiveness and safety of different oral Chinese patent medicine (OCPM) versus oxaliplatin-based chemotherapy regimen (C) alone for colorectal cancer (CRC) through network meta-analysis (NMA). METHODS Several electronic databases were searched for randomized controlled trials (RCTs) concentrated on the use of OCPM to treat CRC with C from the inception of the databases to January 10, 2021. We performed frequentist NMA and indirect comparison to compare study outcomes from the included RCTs. The risk of bias of each study was assessed using the Cochrane risk of bias tool. Confidence in evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). RESULTS A total of 31 RCTs with 1985 participants comparing 10 OCPM, namely, Antike (ATK), Shenyi (SY), Huachansu (HCS), Boerning (BEN), Xiaoaiping (XAP), Jinlong (JL), Compound matrine (CC), Pingxiao (PX), Xihuang pill (XHW), Kangaiping (KAP) were identified. The methodological quality of included RCTs was not very high. The results of the NMA showed that the comparisons were all indirect. Among diverse OCPM, ATK + C had the highest objective response rate (ORR) with a P-score of .63 with risk ratio (RR) of 1.37 (95% CI 1.12-1.66); with a RR of 1.96 (1.26-3.05), SY + C had the highest performance status with a P-score of .73; KAP + C had the lowest nausea and vomiting with a P-score of .91 and with a RR of 0.29 (0.10-0.79); and JL + C had lowest leukopenia with a P-score of .95 with a RR of 0.47 (0.31-0.72). The results of pairwise comparison suggested no difference in outcomes among 10 kinds of OCPM + C. The comparison-adjusted funnel plots suggested that there might not be small-study effects for outcomes. According to the CINeMa approach, the confidence rating of this NMA ranged from "very low" to "low" for various comparisons. CONCLUSION Based on the NMA, ATK + C, SY + C, KAP + C and JL + C were associated with more preferable and options for CRC patients when referring to ORR, performance status, nausea and vomiting, and leukopenia, respectively. However, owing to the limitations of this research, the above conclusions require further verification by more high-quality RCTs. PROSPERO REGISTRATION CRD42020160658.
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Affiliation(s)
- Mo Tang
- China Academy of Chinese Medical
Sciences, Beijing, China
| | - Bin He
- China Academy of Chinese Medical
Sciences, Beijing, China
| | - Jiawei Zhai
- China Academy of Chinese Medical
Sciences, Beijing, China
| | - Lei Wang
- China Academy of Chinese Medical
Sciences, Beijing, China
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8
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Chen J, Zhang Y, Meng Z, Guo L, Yuan X, Zhang Y, Chai Y, Sessler JL, Meng Q, Li C. Supramolecular combination chemotherapy: a pH-responsive co-encapsulation drug delivery system. Chem Sci 2020; 11:6275-6282. [PMID: 32953023 PMCID: PMC7473403 DOI: 10.1039/d0sc01756f] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/01/2020] [Indexed: 12/23/2022] Open
Abstract
Most cancer chemotherapy regimens rely on the use of two or more chemotherapeutic agents. However, achieving the best possible dosing of the individual drugs can be challenging due to differences in metabolism, uptake, and clearance among other factors. Here we describe a supramolecular strategy for achieving drug delivery in which the loading ratio of two active components is easily defined. Specifically, we report the formation of aggregates comprised of self-assembled amphiphiles between carboxylatopillar[6]arene (CP6A) and an oxaliplatin (OX)-type Pt(iv) prodrug (PtC10). The association constant (K a) for the underlying host-guest interaction at pH 7.4 ((1.16 ± 0.03) × 104 M-1) is an order of magnitude higher than at pH 5.0 ((1.73 ± 0.15) × 103 M-1). A second chemotherapeutic, doxorubicin (DOX), may be encapsulated in the resulting vesicles (PtC10⊂CP6A) to give a supramolecular combination chemotherapeutic system DOX@PtC10⊂CP6A. Drug release studies served to confirm that PtC10 and DOX are released in acidic environments. Support for a synergistic antiproliferative effect relative to PtC10 + DOX came from cellular studies of DOX@PtC10⊂CP6A using the human liver hepatocellular carcinoma (HepG-2) cell line. In vivo studies revealed that DOX@PtC10⊂CP6A is not only able to retard tumor growth efficiently but also reduce drug-related toxic side effects in BALB/c nude mice bearing HepG-2 subcutaneous tumor xenografts. These favorable findings are attributed to the formation of a ternary complex that benefits from an enhanced permeability and retention (EPR) effect in vivo while allowing for the pH-based release of PtC10 and DOX at the tumor site.
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Affiliation(s)
- Junyi Chen
- State Key Laboratory of Toxicology and Medical Countermeasures , Beijing Institute of Pharmacology and Toxicology , Beijing 100850 , P. R. China .
- Department of Chemistry , Center for Supramolecular Chemistry and Catalysis , Shanghai University , Shanghai 200444 , P. R. China .
| | - Yadan Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures , Beijing Institute of Pharmacology and Toxicology , Beijing 100850 , P. R. China .
| | - Zhao Meng
- State Key Laboratory of Toxicology and Medical Countermeasures , Beijing Institute of Pharmacology and Toxicology , Beijing 100850 , P. R. China .
| | - Lei Guo
- State Key Laboratory of Toxicology and Medical Countermeasures , Beijing Institute of Pharmacology and Toxicology , Beijing 100850 , P. R. China .
| | - Xingyi Yuan
- State Key Laboratory of Toxicology and Medical Countermeasures , Beijing Institute of Pharmacology and Toxicology , Beijing 100850 , P. R. China .
- Department of Chemistry , Center for Supramolecular Chemistry and Catalysis , Shanghai University , Shanghai 200444 , P. R. China .
| | - Yahan Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures , Beijing Institute of Pharmacology and Toxicology , Beijing 100850 , P. R. China .
| | - Yao Chai
- State Key Laboratory of Toxicology and Medical Countermeasures , Beijing Institute of Pharmacology and Toxicology , Beijing 100850 , P. R. China .
- Department of Chemistry , Center for Supramolecular Chemistry and Catalysis , Shanghai University , Shanghai 200444 , P. R. China .
| | - Jonathan L Sessler
- Department of Chemistry , Center for Supramolecular Chemistry and Catalysis , Shanghai University , Shanghai 200444 , P. R. China .
| | - Qingbin Meng
- State Key Laboratory of Toxicology and Medical Countermeasures , Beijing Institute of Pharmacology and Toxicology , Beijing 100850 , P. R. China .
- Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education) , College of Chemistry , Nankai University , Tianjin , 300071 , China
- Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain , Affiliated Ministry of Education , College of Pharmacy , Yanbian University , Yanji , Jilin , 133002 , China
| | - Chunju Li
- Department of Chemistry , Center for Supramolecular Chemistry and Catalysis , Shanghai University , Shanghai 200444 , P. R. China .
- Key Laboratory of Inorganic-Organic Hybrid Functional Material Chemistry , Ministry of Education , Tianjin Key Laboratory of Structure and Performance for Functional Molecules , College of Chemistry , Tianjin Normal University , Tianjin 300387 , P. R. China .
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9
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Duran G, Cruz R, Simoes AR, Barros F, Giráldez JM, Bernárdez B, Anido U, Candamio S, López-López R, Carracedo Á, Lamas MJ. Efficacy and toxicity of adjuvant chemotherapy on colorectal cancer patients: how much influence from the genetics? J Chemother 2020; 32:310-322. [PMID: 32441565 DOI: 10.1080/1120009x.2020.1764281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We studied the predictive value for response and toxicity of functional polymorphisms in genes involved in the oxaliplatin/fluorouracil pathway in colorectal cancer patients. One hundred and twenty-seven (127) patients were treated with curative intended surgery followed by adjuvant chemotherapy with FOLFOX (fluorouracil, leucovorin and oxaliplatin) regimen. The median age was 65.53 (27-80) years (66.9% male, 59.1% rectum). The median follow-up was 8.5 years (IQR, 4.1-9.4). At the end of follow-up, 59 patients (46.5%) had relapsed or died in the whole study population. We did find that XRCC1GG genotype is associated with a higher risk of developing haematologic toxicity. Furthermore, we report a significant association of the TS 3'UTR 6 bp/6 bp polymorphism and the XRCC1 rs25487 with a higher risk of developing anaemia and diarrhoea, respectively. On the other hand, none of the studied polymorphisms showed clinically relevant association with disease-free survival and overall survival or early failure to adjuvant FOLFOX therapy.
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Affiliation(s)
- Goretti Duran
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.,Pharmacy Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
| | - Raquel Cruz
- Center for Biomedical Research on Rare Diseases (CIBERER), Genomics Medicine Group, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ana Rita Simoes
- Fundación Instituto de Investigación Sanitaria de Santiago (FIDIS), Santiago de Compostela, Spain.,Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía, Obstetricia e Pediatría, Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain.,Genomics Medicine Group, Galician Public Foundation of Genomic Medicine (FPGMX), Santiago de Compostela, Spain
| | - Francisco Barros
- Genomics Medicine Group, Galician Public Foundation of Genomic Medicine (FPGMX), Santiago de Compostela, Spain
| | - José María Giráldez
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.,Pharmacy Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
| | - Beatriz Bernárdez
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.,Pharmacy Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
| | - Urbano Anido
- Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain.,Medical Oncology Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
| | - Sonia Candamio
- Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain.,Medical Oncology Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
| | - Rafael López-López
- Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain.,Medical Oncology Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain.,Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain
| | - Ángel Carracedo
- Genomics Medicine Group, CIBERER, Galician Public Foundation of Genomic Medicine (FPGMX), University of Santiago de Compostela, Santiago de Compostela, Spain
| | - María Jesús Lamas
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.,Pharmacy Department, University Hospital of Santiago (SERGAS), Santiago de Compostela, Spain
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10
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Pharmacogenomics, biomarker network, and allele frequencies in colorectal cancer. THE PHARMACOGENOMICS JOURNAL 2019; 20:136-158. [PMID: 31616044 DOI: 10.1038/s41397-019-0102-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 09/09/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is one of the leading causes of cancer death worldwide. Over the last decades, several studies have shown that tumor-related genomic alterations predict tumor prognosis, drug response, and toxicity. These observations have led to the development of several therapies based on individual genomic profiles. As part of these approaches, pharmacogenomics analyses genomic alterations which may predict an efficient therapeutic response. Studying these mutations as biomarkers for predicting drug response is of a great interest to improve precision medicine. We conduct a comprehensive review of the main pharmacogenomics biomarkers and genomic alterations affecting enzyme activity, transporter capacity, channels, and receptors; and therefore the new advances in CRC precision medicine to select the best therapeutic strategy in populations worldwide, with a focus on Latin America.
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11
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Combinational drug-loaded lipid nanocapsules for the treatment of cancer. Int J Pharm 2019; 569:118588. [DOI: 10.1016/j.ijpharm.2019.118588] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 01/15/2023]
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12
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Crisci S, Amitrano F, Saggese M, Muto T, Sarno S, Mele S, Vitale P, Ronga G, Berretta M, Di Francia R. Overview of Current Targeted Anti-Cancer Drugs for Therapy in Onco-Hematology. ACTA ACUST UNITED AC 2019; 55:medicina55080414. [PMID: 31357735 PMCID: PMC6723645 DOI: 10.3390/medicina55080414] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 07/21/2019] [Accepted: 07/24/2019] [Indexed: 12/13/2022]
Abstract
The upgraded knowledge of tumor biology and microenviroment provides information on differences in neoplastic and normal cells. Thus, the need to target these differences led to the development of novel molecules (targeted therapy) active against the neoplastic cells' inner workings. There are several types of targeted agents, including Small Molecules Inhibitors (SMIs), monoclonal antibodies (mAbs), interfering RNA (iRNA) molecules and microRNA. In the clinical practice, these new medicines generate a multilayered step in pharmacokinetics (PK), which encompasses a broad individual PK variability, and unpredictable outcomes according to the pharmacogenetics (PG) profile of the patient (e.g., cytochrome P450 enzyme), and to patient characteristics such as adherence to treatment and environmental factors. This review focuses on the use of targeted agents in-human phase I/II/III clinical trials in cancer-hematology. Thus, it outlines the up-to-date anticancer drugs suitable for targeted therapies and the most recent finding in pharmacogenomics related to drug response. Besides, a summary assessment of the genotyping costs has been discussed. Targeted therapy seems to be an effective and less toxic therapeutic approach in onco-hematology. The identification of individual PG profile should be a new resource for oncologists to make treatment decisions for the patients to minimize the toxicity and or inefficacy of therapy. This could allow the clinicians to evaluate benefits and restrictions, regarding costs and applicability, of the most suitable pharmacological approach for performing a tailor-made therapy.
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Affiliation(s)
- Stefania Crisci
- Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale" IRCCS, Naples 80131, Italy
| | - Filomena Amitrano
- Gruppo Oncologico Ricercatori Italiano GORI ONLUS, Pordenone 33100, Italy
| | - Mariangela Saggese
- Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale" IRCCS, Naples 80131, Italy
| | - Tommaso Muto
- Hematology and Cellular Immunology (Clinical Biochemistry) A.O. dei Colli Monaldi Hospital, Naples 80131, Italy
| | - Sabrina Sarno
- Anatomia Patologica, Istituto Nazionale Tumori, Fondazione "G. Pascale" IRCCS, Naples 80131, Italy
| | - Sara Mele
- Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale" IRCCS, Naples 80131, Italy
| | - Pasquale Vitale
- Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale" IRCCS, Naples 80131, Italy
| | - Giuseppina Ronga
- Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale" IRCCS, Naples 80131, Italy
| | - Massimiliano Berretta
- Department of Medical Oncology, CRO National Cancer Institute, Aviano (PN) 33081, Italy
| | - Raffaele Di Francia
- Italian Association of Pharmacogenomics and Molecular Diagnostics (IAPharmagen), Ancona 60125, Italy.
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13
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Hu X, Qin W, Li S, He M, Wang Y, Guan S, Zhao H, Yao W, Wei M, Liu M, Wu H. Polymorphisms in DNA repair pathway genes and ABCG2 gene in advanced colorectal cancer: correlation with tumor characteristics and clinical outcome in oxaliplatin-based chemotherapy. Cancer Manag Res 2018; 11:285-297. [PMID: 30643454 PMCID: PMC6312053 DOI: 10.2147/cmar.s181922] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Objective Multiple factors are involved in oxaliplatin-resistant process in colorectal cancer (CRC) patients including decreased drug accumulation and enhanced capacity to repair and tolerate DNA damage. In the present study, we aimed to assess the impact of six single-nucleotide polymorphisms (SNPs) in DNA repair genes and ABCG2 gene on prognosis in advanced CRC patients treated with oxaliplatin-based chemotherapy. Methods In this study, 580 advanced CRC patients were recruited. Six SNPs of DNA repair genes (XPA rs10817938, XPA rs2808668, XPC rs2607775, and WRN rs1346044) and ABCG2 gene (rs2231142 and rs2622621) were genotyped by using the TaqMan assay. Results Regarding interaction with environmental factors, ABCG2 rs2231142 and the first-degree family history of cancer and XPC rs2607775 or ABCG2 rs2622621 and lymph node metastases status demonstrated significant interactions. Of these six SNPs, XPA rs10817938 CT/ TT genotypes retained its significant association with longer overall survival (OS) (P=0.008) in CRC patients receiving oxaliplatin-based chemotherapy (n=580). Furthermore, a significantly better impact on the disease-free survival (DFS) (P=0.001) and OS (P<0.0001) was found in ABCG2 rs2231142CA/AA carriers. Furthermore, ABCG2 rs2622621 CG/GG genotype was verified to be an independent poor prognostic factor in DFS (P=0.010) and OS (P=0.030). In the stratification analysis, XPA rs10817938 CT/CC, rs2231142 CA/AA, and rs2622621 CC genotypes of ABCG2 were predictive of significantly better prognosis in the patients with tumor differentiation grade 3 (n=523), clinical stage IV (n=73), or lymph node-positive status (n=557). Additionally, multivariate logistic regression and multiple dimension reduction analysis consistently revealed that the combination of selected SNPs and five known risk factors showed a better prediction prognosis and represented the best model to predict CRC prognosis. Conclusion The current data indicated that the XPA gene and ABCG2 gene had significant interaction with environmental factors and prognosis, which could provide a comprehensive understanding of the implications of those SNPs in the prediction of prognosis in advanced CRC patients receiving oxaliplatin-based chemotherapy.
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Affiliation(s)
- Xiaoyun Hu
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China, ;
| | - Wenyan Qin
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China, ;
| | - Shanqiong Li
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China, ;
| | - Miao He
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China, ;
| | - Yilin Wang
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China, ;
| | - Shu Guan
- Department of Breast Surgery, First Hospital of China Medical University, Shenyang 110001, China
| | - Haishan Zhao
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China, ;
| | - Weifan Yao
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China, ;
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China, ;
| | - Mingyan Liu
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China, ;
| | - Huizhe Wu
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang 110122, China, ;
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14
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Di Francia R, Atripaldi L, Di Martino S, Fierro C, Muto T, Crispo A, Rossetti S, Facchini G, Berretta M. Assessment of Pharmacogenomic Panel Assay for Prediction of Taxane Toxicities: Preliminary Results. Front Pharmacol 2017; 8:797. [PMID: 29163177 PMCID: PMC5682021 DOI: 10.3389/fphar.2017.00797] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 10/20/2017] [Indexed: 01/06/2023] Open
Abstract
Backbone: Paclitaxel and docetaxel are the primary taxane anticancer drugs regularly used to treat, breast, gastric, ovarian, head/neck, lung, and genitourinary neoplasm. Suspension of taxane treatments compromising patient benefits is more frequently caused by peripheral neuropathy and allergy, than to tumor progression. Several strategies for preventing toxicity have been investigated so far. Recently, findings on the genetic variants associated with toxicity and resistance to taxane-based chemotherapy have been reported. Methods: An extensive panel of five polymorphisms on four candidate genes (ABCB1, CYP2C8*3, CYP3A4*1B, XRCC3), previously validated as significant markers related to paclitaxel and Docetaxel toxicity, are analyzed and discussed. We genotyped 76 cancer patients, and 35 of them received paclitaxel or docetaxel-based therapy. What is more, an early outline evaluation of the genotyping costs and benefit was assessed. Results: Out of 35 patients treated with a taxane, six (17.1%) had adverse neuropathy events. Pharmacogenomics analysis showed no correlation between candidate gene polymorphisms and toxicity, except for the XRCC3 AG+GG allele [OR 2.61 (95% CI: 0.91–7.61)] which showed a weak significant trend of risk of neurotoxicities vs. the AG allele [OR 1.52 (95% CI: 0.51–4.91)] P = 0.03. Summary: Based on our experimental results and data from the literature, we propose a useful and low-cost genotyping panel assay for the prevention of toxicity in patients undergoing taxane-based therapy. With the individual pharmacogenomics profile, clinicians will have additional information to plan the better treatment for their patients to minimize toxicity and maximize benefits, including determining cost-effectiveness for national healthcare sustainability.
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Affiliation(s)
- Raffaele Di Francia
- Hematology-Oncology Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale" IRCCS, Napoli, Italy
| | - Luigi Atripaldi
- Hematology and Cellular Immunology (Clinical Biochemistry), A.O. dei Colli Monaldi Hospital, Naples, Italy
| | | | - Carla Fierro
- Hematology and Cellular Immunology (Clinical Biochemistry), A.O. dei Colli Monaldi Hospital, Naples, Italy
| | - Tommaso Muto
- Hematology and Cellular Immunology (Clinical Biochemistry), A.O. dei Colli Monaldi Hospital, Naples, Italy
| | - Anna Crispo
- Epidemiology-Oncology Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale" IRCCS, Napoli, Italy
| | - Sabrina Rossetti
- Medical Oncology Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale", Napoli, Italy
| | - Gaetano Facchini
- Medical Oncology Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale", Napoli, Italy
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15
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Pulvers JN, Marx G. Factors associated with the development and severity of oxaliplatin-induced peripheral neuropathy: a systematic review. Asia Pac J Clin Oncol 2017; 13:345-355. [PMID: 28653815 DOI: 10.1111/ajco.12694] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 03/27/2017] [Indexed: 11/30/2022]
Abstract
Oxaliplatin is a platinum-derivative chemotherapeutic agent used for colorectal cancer in the adjuvant and metastatic setting in combination with folinic acid and 5-fluorouracil. Oxaliplatin causes an acute cold-induced neurotoxicity and a chronic cumulative neuropathy, which can require dose modification and impact quality of life. To date, no prevention and treatment strategies have proved effective thus reinforcing the importance of identifying at-risk patients in order to maximize therapeutic benefit while minimizing neurotoxicity. Here we reviewed studies on risk and prognostic factors associated with the development and severity of oxaliplatin-induced peripheral neuropathy. A systematic search was conducted in MEDLINE and Embase, and studies investigating clinical and patient-related factors associated with oxaliplatin-induced peripheral neuropathy as their primary focus were identified, and quantitative data were extracted when available. We identified 15 studies, of which only three were prospective. Notable factors were acute neurotoxicity symptoms predicting chronic neuropathy, baseline laboratory findings, patient demographics such as age and gender, comorbidities, and environmental factors. No factor was consistently identified across multiple studies other than the association with oxaliplatin dose. Further investigation into these factors may yield insight into potential neuropathy prevention and treatment strategies.
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Affiliation(s)
| | - Gavin Marx
- Sydney Medical School, University of Sydney, NSW, Australia.,Sydney Adventist Hospital, Wahroonga, NSW, Australia
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16
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Bahrami A, Amerizadeh F, Hassanian SM, ShahidSales S, Khazaei M, Maftouh M, Ghayour-Mobarhan M, Ferns GA, Avan A. Genetic variants as potential predictive biomarkers in advanced colorectal cancer patients treated with oxaliplatin-based chemotherapy. J Cell Physiol 2017; 233:2193-2201. [DOI: 10.1002/jcp.25966] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 04/18/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Afsane Bahrami
- Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences; Mashhad Iran
- Student Research Committee, Faculty of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Forouzan Amerizadeh
- Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences; Mashhad Iran
- Student Research Committee, Faculty of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center; Mashhad University of Medical Sciences; Mashhad Iran
- Department of Medical Biochemistry, Faculty of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | | | - Majid Khazaei
- Department of Physiology, Faculty of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Mina Maftouh
- Metabolic Syndrome Research Center; Mashhad University of Medical Sciences; Mashhad Iran
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center; Mashhad University of Medical Sciences; Mashhad Iran
| | - Gordon A. Ferns
- Brighton & Sussex Medical School; Division of Medical Education; Falmer Brighton, Sussex UK
| | - Amir Avan
- Metabolic Syndrome Research Center; Mashhad University of Medical Sciences; Mashhad Iran
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17
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Mayr J, Heffeter P, Groza D, Galvez L, Koellensperger G, Roller A, Alte B, Haider M, Berger W, Kowol CR, Keppler BK. An albumin-based tumor-targeted oxaliplatin prodrug with distinctly improved anticancer activity in vivo. Chem Sci 2016; 8:2241-2250. [PMID: 28507680 PMCID: PMC5409245 DOI: 10.1039/c6sc03862j] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 12/02/2016] [Indexed: 01/03/2023] Open
Abstract
An oxaliplatin-based platinum(iv) drug which specifically binds to albumin after i.v. application led to several complete responses in tumor-bearing mice.
The design of targeted platinum(iv) prodrugs is a very promising approach to enhance the low selectivity of platinum(ii) drugs towards cancerous tissue in order to reduce the impact on healthy tissue and, consequently, the often severe side-effects. Herein, we report a set of mono-functionalized cis- and oxaliplatin-based platinum(iv) complexes bearing a maleimide moiety, which allows selective binding to serum albumin in the bloodstream. This leads not only to a prolonged plasma half-life by avoidance of fast renal clearance, but also to preferential accumulation of the drug in the tumor tissue due to the EPR-effect. Additionally, analogous succinimide-functionalized derivatives were prepared to verify the influence of the maleimide moiety. First experiments showed that all the maleimide compounds are stable and also possess good albumin-binding properties in whole serum. Further analytical studies on in vivo samples proved the highly increased plasma half-life, as well as tumor accumulation of the maleimide-functionalized substances. In vivo antitumor experiments with CT-26-bearing mice showed that, in contrast to the cisplatin derivatives, the oxaliplatin-based complexes had exceptionally better activity than the free drug resulting in the cure of the majority of treated mice. Subsequent analysis suggested that a distinctly faster reduction as well as reduced tumor accumulation of the cisplatin derivative might explain the worse performance compared to the oxaliplatin(iv) complexes. Taken together, a novel lead platinum(iv) complex with outstanding antitumor activity is presented, which will now be further developed towards clinical phase I trials.
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Affiliation(s)
- Josef Mayr
- University of Vienna , Institute of Inorganic Chemistry , Waehringer Strasse 42 , A-1090 , Vienna , Austria . ; ; Tel: +43-1-4277-52609
| | - Petra Heffeter
- Institute of Cancer Research and Comprehensive Cancer Center , Medical University of Vienna , Borschkegasse 8a , A-1090 , Vienna , Austria . ; ; Tel: +43-1-40160-57557.,Research Platform "Translational Cancer Therapy Research" , University of Vienna , Waehringer Strasse 42 , A-1090 , Vienna , Austria
| | - Diana Groza
- Institute of Cancer Research and Comprehensive Cancer Center , Medical University of Vienna , Borschkegasse 8a , A-1090 , Vienna , Austria . ; ; Tel: +43-1-40160-57557
| | - Luis Galvez
- University of Vienna , Institute of Analytical Chemistry , Waehringer Strasse 38 , A-1090 , Vienna , Austria
| | - Gunda Koellensperger
- University of Vienna , Institute of Analytical Chemistry , Waehringer Strasse 38 , A-1090 , Vienna , Austria
| | - Alexander Roller
- University of Vienna , Institute of Inorganic Chemistry , Waehringer Strasse 42 , A-1090 , Vienna , Austria . ; ; Tel: +43-1-4277-52609
| | - Beatrix Alte
- University of Vienna , Institute of Inorganic Chemistry , Waehringer Strasse 42 , A-1090 , Vienna , Austria . ; ; Tel: +43-1-4277-52609.,Institute of Cancer Research and Comprehensive Cancer Center , Medical University of Vienna , Borschkegasse 8a , A-1090 , Vienna , Austria . ; ; Tel: +43-1-40160-57557
| | - Melanie Haider
- Institute of Cancer Research and Comprehensive Cancer Center , Medical University of Vienna , Borschkegasse 8a , A-1090 , Vienna , Austria . ; ; Tel: +43-1-40160-57557
| | - Walter Berger
- Institute of Cancer Research and Comprehensive Cancer Center , Medical University of Vienna , Borschkegasse 8a , A-1090 , Vienna , Austria . ; ; Tel: +43-1-40160-57557.,Research Platform "Translational Cancer Therapy Research" , University of Vienna , Waehringer Strasse 42 , A-1090 , Vienna , Austria
| | - Christian R Kowol
- University of Vienna , Institute of Inorganic Chemistry , Waehringer Strasse 42 , A-1090 , Vienna , Austria . ; ; Tel: +43-1-4277-52609.,Research Platform "Translational Cancer Therapy Research" , University of Vienna , Waehringer Strasse 42 , A-1090 , Vienna , Austria
| | - Bernhard K Keppler
- University of Vienna , Institute of Inorganic Chemistry , Waehringer Strasse 42 , A-1090 , Vienna , Austria . ; ; Tel: +43-1-4277-52609.,Research Platform "Translational Cancer Therapy Research" , University of Vienna , Waehringer Strasse 42 , A-1090 , Vienna , Austria
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18
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Liu R, Huang M, Zhao X, Peng W, Sun S, Cao J, Ji D, Wang C, Guo W, Li J, Yin J, Zhu X. Neutropenia predicts better prognosis in patients with metastatic gastric cancer on a combined epirubicin, oxaliplatin and 5-fluorouracil regimen. Oncotarget 2016; 6:39018-27. [PMID: 26528696 PMCID: PMC4770753 DOI: 10.18632/oncotarget.5730] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 10/06/2015] [Indexed: 12/26/2022] Open
Abstract
Chemotherapy-induced neutropenia (CIN) reportedly indicated better prognosis for some cancers. We retrospectively analyzed 150 evaluable metastatic gastric cancer (MGC) patients who had received first-line EOF5 (combination regimen of epirubicin, oxaliplatin and 5-day continuous infusion of 5-fluorouracil) treatment. We divided patients into three groups according to the worst grade of CIN: absent group (grade 0), moderate group (grade 1–2) and severe group (grade 3–4). Multivariate analyses of overall survival (OS) proved moderate and severe CIN were important prognostic factors whether regarding CIN as a time-varying covariate (TVC) or not. Compared with absent CIN, hazard ratio (HR) for moderate and severe CIN were 0.31 (95% confidential interval (CI): 0.17–0.55; P < 0.001) and 0.36 (95% CI: 0.20–0.64; P = 0.001) respectively with TVC; and were 0.31 (95% CI: 0.17–0.56; P < 0.001) and 0.34 (95% CI: 0.19–0.61; P < 0.001) respectively without TVC. In progression-free survival (PFS) analyses, moderate and severe CIN showed similar results. In the landmark group (n = 122 patients) analyses with TVC, moderate and severe CIN remained prognostic factors for PFS, while only moderate CIN was prognostic factor for OS. CIN predicted longer OS and PFS in MGC patients treated with first-line EOF5 chemotherapy.
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Affiliation(s)
- Rujiao Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Mingzhu Huang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Xiaoying Zhao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Wei Peng
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Si Sun
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Jun Cao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Dongmei Ji
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Chenchen Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Jiliang Yin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Xiaodong Zhu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
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19
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Berretta M, Di Francia R, Stanzione B, Facchini G, LLeshi A, De Paoli P, Spina M, Tirelli U. New treatment strategies for HIV-positive cancer patients undergoing antiblastic chemotherapy. Expert Opin Pharmacother 2016; 17:2391-2403. [PMID: 27771974 DOI: 10.1080/14656566.2016.1252332] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the outcome of HIV-infected patients by prolonging their survival. The increase in life expectancy has led to an increased risk of non-AIDS-related mortality and morbidity, including cardiovascular diseases, neurocognitive diseases, neuroendocrine dysfunctions and cancer. Areas covered: The GICAT (Italian Cooperation Group on AIDS and Tumors) has demonstrated that patients who receive a multidisciplinary approach with the combination of anticancer agents (AC) and HAART can achieve better responses and survival rates than patients who receive AC alone. The first obstacle for the oncologist to plan treatment for cancer HIV-patients is the preliminary evaluation of drug-drug interactions between AC and HAART. Recent progress in pharmacogenomics could provide a new approach for personalized treatments. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, to maximize the efficacy of both concomitant therapy and to minimize the risk of DDIs, a currently useful list of pharmacogenomic markers of key metabolic enzymes is provided. Expert opinion: In this scenario, the importance of cooperation between oncologists and other health specialists (i.e., infectivologists, pharmacists, genetics and lab specialists) must not be underestimated in the management of these patients with the aim of planning an individual treatment strategy.
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Affiliation(s)
| | - Raffaele Di Francia
- b Hematology-Oncology and Stem Cell Transplantation Unit , National Cancer Institute, Fondazione 'G. Pascale' IRCCS , Naples , Italy
| | - Brigida Stanzione
- a Department of Medical Oncology , National Cancer Institute , Aviano , Italy
| | - Gaetano Facchini
- c Division of Medical Oncology, Department of Uro-Gynecological Oncology , Istituto Nazionale Tumori 'Fondazione G. Pascale' - IRCCS , Naples , Italy
| | - Arben LLeshi
- a Department of Medical Oncology , National Cancer Institute , Aviano , Italy
| | - Paolo De Paoli
- d Scientific Directorate , National Cancer Institute , Aviano , Italy
| | - Michele Spina
- a Department of Medical Oncology , National Cancer Institute , Aviano , Italy
| | - Umberto Tirelli
- a Department of Medical Oncology , National Cancer Institute , Aviano , Italy
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20
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Berretta M, Caraglia M, Martellotta F, Zappavigna S, Lombardi A, Fierro C, Atripaldi L, Muto T, Valente D, De Paoli P, Tirelli U, Di Francia R. Drug-Drug Interactions Based on Pharmacogenetic Profile between Highly Active Antiretroviral Therapy and Antiblastic Chemotherapy in Cancer Patients with HIV Infection. Front Pharmacol 2016; 7:71. [PMID: 27065862 PMCID: PMC4811911 DOI: 10.3389/fphar.2016.00071] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 03/10/2016] [Indexed: 01/08/2023] Open
Abstract
The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the natural approach of HIV-related cancers. Several studies have shown that intensive antiblastic chemotherapy (AC) is feasible in HIV-infected patients with cancer, and that the outcome is similar to that of HIV-negative patients receiving the same AC regimens. However, the concomitant use of HAART and AC can result in drug accumulation or possible toxicity with consequent decreased efficacy of one or both classes of drugs. In fact, many AC agents are preferentially metabolized by CYP450 and drug-drug interactions (DDIs) with HAART are common. Therefore, it is important that HIV patients with cancer in HAART receiving AC treatment at the same time receive an individualized cancer management plan based on their liver and renal functions, their level of bone marrow suppression, their mitochondrial dysfunction, and their genotype profile. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, in order to maximize the efficacy of antiblastic therapy and minimize the risk of drug-drug interaction, a useful list of pharmacogenomic markers is provided.
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Affiliation(s)
| | - Michele Caraglia
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples Naples, Italy
| | | | - Silvia Zappavigna
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples Naples, Italy
| | - Angela Lombardi
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples Naples, Italy
| | - Carla Fierro
- Hematology and Cellular Immunology (Clinical Biochemistry), A.O. dei Colli Monaldi Hospital Naples, Italy
| | - Luigi Atripaldi
- Hematology and Cellular Immunology (Clinical Biochemistry), A.O. dei Colli Monaldi Hospital Naples, Italy
| | - Tommaso Muto
- Hematology and Cellular Immunology (Clinical Biochemistry), A.O. dei Colli Monaldi Hospital Naples, Italy
| | - Daniela Valente
- Molecular Diagnostics Service, CETAC Research Center Caserta, Italy
| | - Paolo De Paoli
- Department of Medical Oncology, CRO National Cancer Institute Aviano, Italy
| | - Umberto Tirelli
- Department of Medical Oncology, CRO National Cancer Institute Aviano, Italy
| | - Raffaele Di Francia
- Hematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione "G. Pascale" IRCCS Naples, Italy
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Liu L, Bai Z, Ma X, Wang T, Yang Y, Zhang Z. Effects of taxol resistance gene 1 expression on the chemosensitivity of SGC-7901 cells to oxaliplatin. Exp Ther Med 2016; 11:846-852. [PMID: 26998002 PMCID: PMC4774308 DOI: 10.3892/etm.2016.2994] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 11/25/2015] [Indexed: 12/17/2022] Open
Abstract
The present study aimed to evaluate the role of taxol resistance gene 1 (Txr1) in the development of oxaliplatin (L-OHP) resistance in gastric cancer (GC). Using SGC-7901 cells as a model, Txr1 was exogenously expressed or knocked down using small interfering RNA. Quantitative polymerase chain reaction (qPCR) and western blotting were performed to establish whether the Txr1 gene is involved in chemoresistance, and cell proliferation was assessed using an MTS assay. To this end, the mRNA and protein levels of Txr1, thrombospondin-1 and excision repair cross-complementing 1 protein were measured using qPCR and western blotting, respectively. Txr1-knockdown significantly increased the sensitivity of the SGC-7901 cells to L-OHP, whereas Txr1 overexpression promoted the resistance of the SGC-7901 cells to L-OHP. Exogenous Txr1 expression in the SGC-7901 cells induced L-OHP resistance, and the siRNA knockdown of Txr1 sensitized the human GC cells to L-OHP. Txr1 is, therefore, likely to play a role in L-OHP resistance, acting via TSP1, and should be investigated as a potential therapeutic target in the treatment of GC.
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Affiliation(s)
- Liancheng Liu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Zhigang Bai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Beijing 100050, P.R. China
| | - Xuemei Ma
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Beijing 100050, P.R. China
| | - Tingting Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Beijing 100050, P.R. China
| | - Yao Yang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Beijing 100050, P.R. China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Beijing 100050, P.R. China
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Liu J, Xu J. Clinical value of capecitabine maintenance therapy after first-line combination chemotherapy in patients with unresectable stage Ⅳ rectal cancer. Shijie Huaren Xiaohua Zazhi 2016; 24:467-473. [DOI: 10.11569/wcjd.v24.i3.467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy and safety of capecitabine maintenance therapy after first-line combination chemotherapy in patients with unresectable stage Ⅳ rectal cancer.
METHODS: Fifty-three patients with unresectable stage Ⅳ advanced rectal cancer who achieved clinical response after first-line chemotherapy (FOLFOX or FOLFIRI, q2w, 12 cycles) from June 2011 to June 2014 at the People's Hospital of Ji'an City were randomly divided into two groups: A and B. Group A (28 patients) received maintenance therapy with capecitabine (1000 mg/m2, po, bid, d1-14, q21d). Group B (25 patients) did not receive any further chemotherapy. Progression-free survival (PFS) and adverse reactions were compared between the two groups.
RESULTS: The 28 patients treated with capecitabine maintenance therapy achieved a median progression free survival (PFS) of around 11.6 mo, significantly longer than the value (6.5 mo) in the 25 patients who did not receive maintenance treatment (P < 0.05). The response rate (RR) after first-line chemotherapy was 39.2% in the maintenance group and 32% in the non-maintenance group (P > 0.05). The adverse effects were reduced significantly in the maintenance therapy group and control group compared with those in first-line combination chemotherapy (P < 0.05). There was no statistical difference in adverse effects between the maintenance treatment and observation groups except for hand-foot syndrome and pigmentation (P > 0.05).
CONCLUSION: Patients with unresectable stage Ⅳ rectal cancer could benefit from capeciabine maintenance therapy in terms of longer PFS, better tolerance and milder adverse reactions.
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Hassan Z, Mustafa S, Rahim RA, Isa NM. Anti-breast cancer effects of live, heat-killed and cytoplasmic fractions of Enterococcus faecalis and Staphylococcus hominis isolated from human breast milk. In Vitro Cell Dev Biol Anim 2015; 52:337-348. [PMID: 26659392 DOI: 10.1007/s11626-015-9978-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 11/08/2015] [Indexed: 11/25/2022]
Abstract
Development of tumour that is resistant to chemotherapeutics and synthetic drugs, coupled with their life-threatening side effects and the adverse effects of surgery and hormone therapies, led to increased research on probiotics' anticancer potentials. The current study investigated the potential of live, heat-killed cells (HKC) and the cytoplasmic fractions (CF) of Enterococcus faecalis and Staphylococcus hominis as anti-breast cancer agents. MCF-7 cell line was treated with 25, 50, 100 and 200 μg/mL each of live, HKC and CF of the bacteria; and cytotoxicity was evaluated for 24, 48 and 72 h using MTT assay. The morphological features of the treated cells were examined by fluorescence microscopy. The stage of cell cycle arrest and apoptosis were quantified by flow cytometry. The bacterial effect on non-malignant breast epithelial cell line, MCF-10A, was assessed using MTT assay for 24, 48 and 72 h. All the three forms of the bacteria caused a significant decrease in MCF-7 (up to 33.29%) cell proliferation in concentration- and time-dependent manner. Morphological features of apoptosis like cell death, cell shrinkage and membrane blebbing were observed. Flow cytometry analyses suggested that about 34.60% of treated MCF-7 was undergoing apoptosis. A strong anti-proliferative activity was efficiently induced through sub-G1 accumulation (up to 83.17%) in treated MCF-7 and decreased number in the G0/G1 phase (74.39%). MCF-10A cells treated with both bacteria showed no significant difference with the untreated (>90% viability). These bacteria can be used as good alternative nutraceutical with promising therapeutic indexes for breast cancer because of their non-cytotoxic effects to normal cells.
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Affiliation(s)
- Zubaida Hassan
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Shuhaimi Mustafa
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia
- Halal Products Research Institute, Universiti Putra Malaysia, Serdang, Malaysia
| | - Raha Abdul Rahim
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Nurulfiza Mat Isa
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia.
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Klahan S, Huang CC, Chien SC, Wu MS, Wong HSC, Huang CY, Chang WC, Wei PL. Bioinformatic analyses revealed underlying biological functions correlated with oxaliplatin responsiveness. Tumour Biol 2015; 37:583-90. [PMID: 26232912 DOI: 10.1007/s13277-015-3807-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 07/20/2015] [Indexed: 11/27/2022] Open
Abstract
Colorectal cancer is one of the most common cancers worldwide. Surgery is usually the primary treatment for colon cancers that have not spread to distant sites. However, chemotherapy may be considered after surgery to eliminate remaining cancer cells or in case the cancer has a high risk of recurrence. Oxaliplatin is often used in combination regimens such as FOLFOX, CapeOX, and FOLFOXIRI because of the cost-effectiveness of adjuvant treatment for patients and also the good tolerability profile. However, some patients show resistance to oxaliplatin which causes poor treatment outcomes. Most colon cancer studies focused on treatments and patient survival. Some studies focused on genetic associations of specific genes. However, pathway and network analyses of oxaliplatin resistance in colon cancer cells using gene expression patterns are still lacking. We performed a microarray analysis and found that endothelin-1 (EDN1), dishevelled segment polarity protein (DV1), toll-like receptor 5(TLR5), mitogen-activated protein kinase 3 (MAP2K3), phosphatidylinositol-4,5-bisphosphate 3-kinase, and catalytic subunit beta (PIK3CB) were closely related to responsiveness to oxaliplatin treatment. Furthermore, we found that the signal transduction, melanogenesis, and toll-like receptor signaling pathways might be involved in oxaliplatin-resistant colon cancer. These genes and pathways might be potential targets for improving oxaliplatin treatment in colon cancer patients.
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Affiliation(s)
- Sukhontip Klahan
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Chi-Cheng Huang
- Department of Surgery, Cathay General Hospital, SiJhih, New Taipei City, Taiwan
- School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
- School of Medicine, Taipei Medical University, Taipei City, Taiwan
| | - Shu-Chen Chien
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Mei-Shin Wu
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Henry Sung-Ching Wong
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Chien-Yu Huang
- Division of General Surgery, Department of Surgery, Department of Neurosurgery Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Wei-Chiao Chang
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
| | - Po-Li Wei
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
- Division of General Surgery, Department of Surgery, Department of Neurosurgery Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
- Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
- Cancer Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
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25
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AlGizawy SM, Essa HH, Ahmed BM. Chemotherapy Alone for Patients With Stage II/III Rectal Cancer Undergoing Radical Surgery. Oncologist 2015; 20:752-7. [PMID: 26040621 DOI: 10.1634/theoncologist.2015-0038] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 03/23/2015] [Indexed: 01/01/2023] Open
Abstract
PURPOSE The purpose of this prospective pilot study was to determine the efficacy of preoperative chemotherapy with six cycles of FOLFOX 6 (without radiation therapy) followed by radical surgery followed by six additional cycles of FOLFOX 6 for patients with stage II/III rectal cancer. PATIENTS AND METHODS From January 2010 to January 2014, patients with locally advanced rectal cancer who met the eligibility criteria were enrolled in this study. Patients received FOLFOX 6 chemotherapy comprising oxaliplatin and leucovorin calcium i.v. over 2 hours on day 1, then bolus, and then continuous fluorouracil i.v. over 46 hours on days 1 and 2. Treatment was repeated every 14 days for 6 courses followed by radical surgery followed by additional 6 cycles of FOLFOX 6. RESULTS In total, 45 patients were enrolled in this study. In the preoperative re-evaluation, the overall response rate was 68.8% (clinical complete response was 4.4%, and the partial response was 64.4%). There were 14 cases (31.2%) of stable disease. No patients had progressive disease. Postoperatively, the pathologic complete response rate was 8 of 45 (17.8%; 95% confidence interval [CI]: 8.9%-28.9%). The median follow-up was 29 months (range 9-54 months). The actuarial 3-year overall survival and disease-free survival rates for all patients were 80.8% (standard error, 1.877; 95% CI: 69.3%-92.3%) and 67.9% (standard error, 2.319; 95% CI: 54.3%-81.5%), respectively. CONCLUSION Neoadjuvant chemotherapy (FOLFOX) without radiotherapy is active and safe but cannot be considered a standard of care until the results of prospective randomized phase III trials are available. IMPLICATIONS FOR PRACTICE Neoadjuvant radiotherapy of rectal cancer represents the current standard of care. However, its use is also associated with short-term toxicity and long-term morbidity. With the increasing use of total mesorectal resection resulting in better local control and advances in systemic therapy for colorectal cancer, this study highlights the question of whether radiation is a necessary component of neoadjuvant therapy for all patients with rectal cancer or whether select patients could be spared the additional toxicities and inconvenience of radiotherapy. This study suggests that neoadjuvant FOLFOX without radiotherapy is active and safe, but it could not be considered a standard of care till now.
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Affiliation(s)
- Samy M AlGizawy
- Department of Clinical Oncology, Faculty of Medicine, and Department of Surgical Oncology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Hoda H Essa
- Department of Clinical Oncology, Faculty of Medicine, and Department of Surgical Oncology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Badawy M Ahmed
- Department of Clinical Oncology, Faculty of Medicine, and Department of Surgical Oncology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
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Kelley MR, Logsdon D, Fishel ML. Targeting DNA repair pathways for cancer treatment: what's new? Future Oncol 2015; 10:1215-37. [PMID: 24947262 DOI: 10.2217/fon.14.60] [Citation(s) in RCA: 141] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Disruptions in DNA repair pathways predispose cells to accumulating DNA damage. A growing body of evidence indicates that tumors accumulate progressively more mutations in DNA repair proteins as cancers progress. DNA repair mechanisms greatly affect the response to cytotoxic treatments, so understanding those mechanisms and finding ways to turn dysregulated repair processes against themselves to induce tumor death is the goal of all DNA repair inhibition efforts. Inhibition may be direct or indirect. This burgeoning field of research is replete with promise and challenge, as more intricacies of each repair pathway are discovered. In an era of increasing concern about healthcare costs, use of DNA repair inhibitors can prove to be highly effective stewardship of R&D resources and patient expenses.
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Affiliation(s)
- Mark R Kelley
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
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27
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Ayaz Ahmed KB, Reshma E, Mariappan M, Anbazhagan V. Spectroscopic investigation on the interaction of ruthenium complexes with tumor specific lectin, jacalin. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2015; 137:1292-1297. [PMID: 25306128 DOI: 10.1016/j.saa.2014.09.047] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 09/06/2014] [Accepted: 09/18/2014] [Indexed: 06/04/2023]
Abstract
Several ruthenium complexes are regarded as anticancer agents and considered as an alternative to the widely used platinum complexes. Owing to the preferential interaction of jacalin with tumor-associated T-antigen, we report the interaction of jacalin with four ruthenium complex namely, tris(1,10-phenanthroline)ruthenium(II)chloride, bis(1,10-phenanthroline)(N-[1,10]phenanthrolin-5-yl-pyrenylmethanimine)ruthenium(II)chloride, bis(1,10-phenanthroline)(dipyrido[3,2-a:2',3'-c]-phenazine)ruthenium(II)chloride, bis(1,10-phenanthroline)(11-(9-acridinyl)dipyrido[3,2-a:2',3'-c]phenazine)ruthenium(II) chloride. Fluorescence spectroscopic analysis revealed that the ruthenium complexes strongly quenched the intrinsic fluorescence of jacalin through a static quenching procedure, and a non-radiative energy transfer occurred within the molecules. Association constants obtained for the interaction of different ruthenium complexes with jacalin are in the order of 10(5) M(-1), which is in the same range as those obtained for the interaction of lectin with carbohydrate and hydrophobic ligand. Each subunit of the tetrameric jacalin binds one ruthenium complex, and the stoichiometry is found to be unaffected by the presence of the specific sugar, galactose. In addition, agglutination activity of jacalin is largely unaffected by the presence of the ruthenium complexes, indicating that the binding sites for the carbohydrate and the ruthenium complexes are different. These results suggest that the development of lectin-ruthenium complex conjugate would be feasible to target malignant cells in chemo-therapeutics.
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Affiliation(s)
- Khan Behlol Ayaz Ahmed
- Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thirumalaisamudaram, Thanjavur, Tamil Nadu, India
| | - Elamvazhuthi Reshma
- Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thirumalaisamudaram, Thanjavur, Tamil Nadu, India
| | - Mariappan Mariappan
- Department of Chemistry, SRM University, Kattankulathur, Chennai, Tamil Nadu, India
| | - Veerappan Anbazhagan
- Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thirumalaisamudaram, Thanjavur, Tamil Nadu, India.
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Kohoutova D, Smajs D, Moravkova P, Cyrany J, Moravkova M, Forstlova M, Cihak M, Rejchrt S, Bures J. Escherichia coli strains of phylogenetic group B2 and D and bacteriocin production are associated with advanced colorectal neoplasia. BMC Infect Dis 2014; 14:733. [PMID: 25540872 PMCID: PMC4300055 DOI: 10.1186/s12879-014-0733-7] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 12/19/2014] [Indexed: 02/07/2023] Open
Abstract
Background Colorectal cancer (CRC) is the 3rd most common cancer worldwide and the Czech Republic has the 6th highest incidence of CRC worldwide. Large intestinal microbiota play in its etiopathogenesis important role. Bacteriocins are proteins, produced by bacteria from the Enterobacteriaceae family. The aim of our prospective study was to assess the colonization of large intestinal mucosa by Escherichia coli strains and to investigate their bacteriocin production. Methods A total of 30 consecutive patients with colorectal adenoma, CRA (17 men, 13 women, aged 39–79, mean age 63 ± 9), 30 patients with CRC (23 men, 7 women, aged 38–86, mean age 67 ± 11) and 20 healthy controls (9 men, 11 women, age 23–84, mean age 55 ± 15) were enrolled into prospective study. Mucosal biopsies were taken in the caecum, transverse colon and rectum during pancolonoscopy. Microbiological culture, isolation and identification of bacteria followed. Bacteriocin production was assessed by growth inhibition of indicator strains E. coli K12-Row, E. coli C6 (phi), and Shigella sonnei 17. Identification of bacteriocin-encoding determinants and E. coli phylogroups was performed using PCR methods. Results A total of 622 strains were isolated and further investigated. A significantly higher frequency of simultaneous production of colicins and microcins was revealed in the group of patients with CRC, when compared to patients with CRA, p = 0.031. A significantly higher frequency of E. coli phylogroup D was found in patients with CRC, when compared to controls, p = 0.044. A significantly higher prevalence of bacteriocinogeny was confirmed in patients with advanced adenoma when compared to patients with non-advanced adenoma, p = 0.010. Increasing bacteriocinogeny was associated with an increasing stage of CRC (assessed according to TNM classification). Either E. coli phylogroup B2 or E. coli phylogroup D were isolated in biopsies of patients with right-sided CRC. A statistically higher incidence of E. coli phylogroup B2 was found in patients with right-sided CRC when compared to patients with left-sided CRC, p = 0.028. Conclusions Large intestinal mucosa of patients with more advanced colorectal neoplasia is colonized with more virulent strains of E. coli and higher production of bacteriocins is observed in these patients when compared to those with less advanced colorectal neoplasia. Electronic supplementary material The online version of this article (doi:10.1186/s12879-014-0733-7) contains supplementary material, which is available to authorized users.
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De Divitiis C, Nasti G, Montano M, Fisichella R, Iaffaioli RV, Berretta M. Prognostic and predictive response factors in colorectal cancer patients: Between hope and reality. World J Gastroenterol 2014; 20:15049-15059. [PMID: 25386053 PMCID: PMC4223238 DOI: 10.3748/wjg.v20.i41.15049] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 03/13/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) represents one of the most commonly diagnosed cancers worldwide. It is the second leading cause of cancer death in Western Countries. In the last decade the survival of patients with metastatic CRC has improved dramatically. Due to the advent of new drugs (irinotecan and oxaliplatin) and target therapies (i.e., bevacizumab, cetuximab and panitumab), the median overall survival has risen from about 12 mo in the mid nineties to 30 mo recently. Many questions needing of right collocations and more clearness still exist regarding the prognostic factors and the predictive factors of response to therapy. Despite advances in dosing and scheduling of chemotherapy in both adjuvant and advanced settings, and a greater emphasis on early detection, the outlook still remains poor for most patients. Molecular analyses have shown that the natural history of all CRCs is not the same. Individual patients with same stage tumours may have different long term prognosis and response to therapy. In addition, some prognostic variables are likely to be more important than others. Here we review the role of prognostic factors and predictive factors according to the recently published English literature.
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