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Marunaka Y, Ohashi T, Kubota T, Nishibeppu K, Konishi H, Shiozaki A, Fujiwara H, Otsuji E. Dropped head syndrome suspected due to oxaliplatin used in adjuvant chemotherapy for gastric cancer: a case report. Surg Case Rep 2024; 10:174. [PMID: 39052137 PMCID: PMC11272757 DOI: 10.1186/s40792-024-01976-w] [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: 06/04/2024] [Accepted: 07/15/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Dropped head syndrome (DHS) is caused by dysfunction of the cervical musculature. It is classified into two groups according to the cause: one is weakness of the neck extensors and the other is hypercontraction of the cervical flexors associated with Parkinson's disease and other disorders. Although some drugs have previously been reported as suspected causes of DHS, we are unaware of any reports in which oxaliplatin was suspected. In this report, we describe a case of DHS during adjuvant chemotherapy for gastric cancer, along with a review of the relevant literature. CASE PRESENTATION A 72-year-old man was diagnosed with gastric cancer, cT3N0M0 cStage IIB, and underwent laparoscopic total gastrectomy with D2 lymphnode dissection and Roux-en-Y reconstruction. The operative time was 311 min, intraoperative blood loss was 40 g, and he was discharged without any post-operative complications. The histopathological diagnosis was pT4aN2M0 pStage IIIA, and S-1 + oxaliplatin (SOX) therapy was started as adjuvant chemotherapy. On the 4th course of SOX, he complained of neck heaviness and a blood test revealed that his creatine kinase (CK) level was elevated to 2464 IU/L. After consultation with an orthopedic surgeon and a neurologist, DHS due to localized cervical extensor myositis was suspected. Therefore, the 6th course of SOX was postponed, and 30 mg of oral steroids were initiated. His symptoms improved, and his CK level decreased within 2 weeks. After resuming S-1 monotherapy and tapering off oral steroids, no recurrence of symptoms has been observed. CONCLUSIONS We experienced one case of DHS during adjuvant chemotherapy for gastric cancer. If DHS develops after starting oxaliplatin, involvement of the drug should be suspected, and discontinuation of chemotherapy and introduction of oral steroids should be considered.
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Affiliation(s)
- Yuta Marunaka
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan.
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Takeshi Kubota
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
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Soliman A, Habibi S, Dasanu CA. Unusual stroke-like symptoms with oxaliplatin use. J Oncol Pharm Pract 2023; 29:1766-1769. [PMID: 37323007 DOI: 10.1177/10781552231181525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
INTRODUCTION Oxaliplatin has become the mainstay of treatment for many cancers, but its use can be accompanied by unusual side effects. CASE REPORT We describe herein a 74-year-old patient with pancreatic cancer who developed severe motor weakness affecting lower extremities after starting treatment with oxaliplatin on three separate occasions. Our patient also experienced slurred speech, with decreased ability to phonate and word-finding difficulty. Brain imaging studies did not suggest recent brain ischemia, and the symptoms resolved within 15-20 h. MANAGEMENT AND OUTCOME Oxaliplatin had to be discontinued due to suboptimal tolerance and a short-lived clinical response. After discontinuation of oxaliplatin, she did not experience any more similar symptoms. A score of 9 on the Naranjo nomogram supported a definite causality relationship between oxaliplatin and the observed neurologic toxicity. DISCUSSION Rare reports of stroke-like events have previously been described with oxaliplatin. While the exact mechanism of these phenomena is not known, alterations in neuronal sodium channels might be involved. Clinicians, pharmacists, and patients need to be aware of these rare but important side effects of oxaliplatin. Nonetheless, work-up for a cerebrovascular accident is still warranted as hypercoagulability related to malignancy can also predispose the patients to strokes.
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Affiliation(s)
- Abram Soliman
- Department of Internal Medicine, Eisenhower Health, Rancho Mirage, CA, USA
| | - Shaghayegh Habibi
- Department of Internal Medicine, Eisenhower Health, Rancho Mirage, CA, USA
| | - Constantin A Dasanu
- Lucy Curci Cancer Center, Eisenhower Health, Rancho Mirage, CA, USA
- Department of Medical Oncology and Hematology, University of California in San Diego Health System, San Diego, CA, USA
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Tsubaki M, Takeda T, Matsuda T, Kishimoto K, Takefuji H, Taniwaki Y, Ueda M, Hoshida T, Tanabe K, Nishida S. Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy. Cancer Cell Int 2023; 23:73. [PMID: 37069612 PMCID: PMC10108455 DOI: 10.1186/s12935-023-02884-z] [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: 11/15/2022] [Accepted: 03/01/2023] [Indexed: 04/19/2023] Open
Abstract
BACKGROUND KRAS mutations are fraught with the progression of colorectal cancer and resistance to chemotherapy. There are pathways such as extracellular regulated protein kinase 1/2 (ERK1/2) and Akt downstream and farnesylation and geranylgeranylation upstream that are activated upon mutated KRAS. Previous studies have shown that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are effective to treat KRAS mutated colorectal cancer cells. Increased doses of oxaliplatin (L-OHP), a well-known alkylating chemotherapeutic drug, causes side effects such as peripheral neuropathy due to ERK1/2 activation in spinal cords. Hence, we examined the combinatorial therapeutic efficacy of statins and L-OHP to reduce colorectal cancer cell growth and abrogate neuropathy in mice. METHODS Cell survival and confirmed apoptosis was assessed using WST-8 assay and Annexin V detection kit. Detection of phosphorylated and total proteins was analyzed the western blotting. Combined effect of simvastatin and L-OHP was examined the allograft mouse model and L-OHP-induced neuropathy was assessed using cold plate and von Frey filament test. RESULTS In this study, we examined the effect of combining statins with L-OHP on induction of cell death in colorectal cancer cell lines and improvement of L-OHP-induced neuropathy in vivo. We demonstrated that combined administration with statins and L-OHP significantly induced apoptosis and elevated the sensitivity of KRAS-mutated colorectal cancer cells to L-OHP. In addition, simvastatin suppressed KRAS prenylation, thereby enhancing antitumor effect of L-OHP through downregulation of survivin, XIAP, Bcl-xL, and Bcl-2, and upregulation of p53 and PUMA via inhibition of nuclear factor of κB (NF-κB) and Akt activation, and induction of c-Jun N-terminal kinase (JNK) activation in KRAS-mutated colorectal cancer cells. Moreover, simvastatin enhanced the antitumor effects of L-OHP and suppressed L-OHP-induced neuropathy via ERK1/2 activation in vivo. CONCLUSION Therefore, statins may be therapeutically useful as adjuvants to L-OHP in KRAS-mutated colorectal cancer and may also be useful in the treatment of L-OHP-induced neuropathy.
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Affiliation(s)
- Masanobu Tsubaki
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Tomoya Takeda
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Takuya Matsuda
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Kana Kishimoto
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Honoka Takefuji
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Yuzuki Taniwaki
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Misa Ueda
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Tadafumi Hoshida
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
- Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan
| | - Kazufumi Tanabe
- Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan
| | - Shozo Nishida
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan.
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Le Gouill-Jaijarat C, Péréon Y, Leroy M, Lépine O, Loloum A, Peluchon C, Volteau C, Martineau AS, Korner S, Perrault C, Benmaziane A, Girot P, Petorin C, Perret C, Ligeza-Poisson C, Mayeur D, Flet L, Chiffoleau A, Poinas A, Bennouna J. PROPERTY: study protocol for a randomized, double-blind, multicenter placebo-controlled trial assessing neurotoxicity in patients with metastatic gastrointestinal cancer taking PHYCOCARE® during oxaliplatin-based chemotherapy. Trials 2023; 24:50. [PMID: 36670495 PMCID: PMC9854012 DOI: 10.1186/s13063-023-07071-z] [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: 12/24/2021] [Accepted: 01/05/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common adverse effects of antineoplastic agents, ranging in prevalence from 19% to over 85%. Clinically, CIPN is a predominantly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. The high prevalence of CIPN among cancer patients makes it a major problem for both patients and survivors, as well as for their health care providers, especially because there is currently no single effective method of preventing CIPN; moreover, the options for treating this syndrome are very limited. Phycocyanin, a biliprotein pigment and an important constituent of the blue-green algae Spirulina platensis, has been reported to possess significant antioxidant and radical-scavenging properties, offering protection against oxidative stress, which is one of the hypothetic mechanisms, between others, of CIPN occurrence. METHODS Our hypothesis is that phycocyanin may give protection against oxaliplatin-induced neuropathy in the treatment of gastrointestinal cancers. Our trial will be a randomized double-blind placebo-controlled study with 110 randomized patients suffering from metastatic gastrointestinal adenocarcinoma including esogastric, colorectal, and pancreatic cancers. Patients are being followed up in the gastroenterology or oncology departments of seven French hospitals. DISCUSSION Due to the neuropathy, patients need to avoid injury by paying careful attention to home safety; patients' physicians often prescribe over-the-counter pain medications. If validated, our hypothesis should help to limit neurotoxicity without the need to discontinue chemotherapy. TRIAL REGISTRATION ClinicalTrials.gov NCT05025826. First published on August 27, 2021.
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Affiliation(s)
- Christele Le Gouill-Jaijarat
- grid.277151.70000 0004 0472 0371Gastroenterology Department, CHU Nantes (Nantes Teaching Hospital), Nantes Université, Nantes, France
| | - Yann Péréon
- grid.277151.70000 0004 0472 0371Department of Clinical Neurophysiology, Reference Centre for Neuromuscular Diseases AOC, Filnemus, Euro-NMD, CHU Nantes, Nantes Université, Place Alexis-Ricordeau, Nantes, France
| | - Maxime Leroy
- grid.277151.70000 0004 0472 0371Sponsor Department, Nantes Université, CHU Nantes, Nantes, France
| | | | | | - Claire Peluchon
- grid.277151.70000 0004 0472 0371Gastroenterology Department, CHU Nantes (Nantes Teaching Hospital), Nantes Université, Nantes, France ,grid.277151.70000 0004 0472 0371Clinical Investigation Centre CIC1413, Nantes Université, CHU Nantes, Inserm, Nantes, France
| | - Christelle Volteau
- grid.277151.70000 0004 0472 0371Sponsor Department, Nantes Université, CHU Nantes, Nantes, France
| | - Anne-Sophie Martineau
- grid.277151.70000 0004 0472 0371Sponsor Department, Nantes Université, CHU Nantes, Nantes, France
| | - Simon Korner
- grid.277151.70000 0004 0472 0371Sponsor Department, Nantes Université, CHU Nantes, Nantes, France
| | - Caroline Perrault
- grid.277151.70000 0004 0472 0371Sponsor Department, Nantes Université, CHU Nantes, Nantes, France
| | - Asmahane Benmaziane
- grid.414106.60000 0000 8642 9959Medical Oncology Department, Hôpital Foch, Paris, France
| | - Paul Girot
- grid.477015.00000 0004 1772 6836Gastroenterology Department, CHD Vendée, La Roche sur Yon, France
| | - Caroline Petorin
- grid.411163.00000 0004 0639 4151CHU Estaing, Clermont-Ferrant, France
| | | | | | - Didier Mayeur
- grid.418037.90000 0004 0641 1257Centre Georges et François Leclerc, Dijon, France
| | - Laurent Flet
- grid.277151.70000 0004 0472 0371Department of Pharmacy, CHU Nantes, Nantes Université, Nantes, France
| | - Anne Chiffoleau
- grid.277151.70000 0004 0472 0371Sponsor Department, Nantes Université, CHU Nantes, Nantes, France
| | - Alexandra Poinas
- grid.277151.70000 0004 0472 0371Clinical Investigation Centre CIC1413, Nantes Université, CHU Nantes, Inserm, Nantes, France
| | - Jaafar Bennouna
- grid.414106.60000 0000 8642 9959Medical Oncology Department, Hôpital Foch, Paris, France
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Chen L, Cao X, Li J, Liu C, Jiang T. Efficacy and safety of metronomic chemotherapy in maintenance therapy for metastatic colorectal cancer: A systematic review of randomized controlled trials. Medicine (Baltimore) 2022; 101:e31659. [PMID: 36401426 PMCID: PMC9678531 DOI: 10.1097/md.0000000000031659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND The current studies on metronomic chemotherapy in mCRC are all aimed at patients after multi-line therapy failure, and only a few studies have focused on maintenance treatment after successful first-line therapy. METHODS The PubMed, Embase, Cochrane Library, Wanfang, CNKI, and VIP were searched, and the relevant data was extracted, including media progression-free survival (mPFS), media overall survival (mOS), and grade 3/4 adverse events (AEs). RESULTS We included 4 randomized controlled trials (RCTs), 2 RCTs showed that metronomic maintenance chemotherapy could significantly improve mPFS compared to observation group; another RCT showed that metronomic maintenance chemotherapy group did not have low mPFS than the bevacizumab maintenance treatment (MT). The final RCT showed that dual-agent metronomic chemotherapy combined with bevacizumab MT did not improve mPFS compared with bevacizumab MT. The 3 RCTs showed that the metronomic maintenance therapy could not effectively improve mOS in mCRC compared to observation group or bevacizumab MT, while another RCT reported that the mOS in metronomic maintenance chemotherapy group was similar to bevacizumab MT. AEs was mostly mild and manageable. Grade ≥ 3 AEs are mostly nonhematological toxicity, and no deaths related to AEs were reported. CONCLUSION This systematic review indicates that metronomic chemotherapy for mCRC MT can improve mPFS in some patients and is relatively safe. However, improvements in OS in most RCTs are arguable. Therefore, we need further studies to verify its long-term efficacy.
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Affiliation(s)
- Li Chen
- Department of Pharmacy, Wusheng People’s Hospital, Wusheng county, Guangan, Sichuan, China
| | - Xin Cao
- General Practice Department, Clinical Medical College and The First Affiliated Hospital of North Sichuan Medical College, Nanchong, SiChuan, China
| | - Jing Li
- Department of Pharmacy, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, SiChuan, China
| | - ChaoMin Liu
- Department of Oncology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, SiChuan, China
- *Correspondence: ChaoMin Liu, Department of Oncology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, 278 Baoguang Street, Xindu District Chengdu 610500, SiChuan, China (e-mail: ); Ting Jiang, Department of Pharmacy, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, 278 Baoguang Street, Xindu District Chengdu 610500, SiChuan, China (e-mail: )
| | - Ting Jiang
- Department of Pharmacy, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, SiChuan, China
- *Correspondence: ChaoMin Liu, Department of Oncology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, 278 Baoguang Street, Xindu District Chengdu 610500, SiChuan, China (e-mail: ); Ting Jiang, Department of Pharmacy, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, 278 Baoguang Street, Xindu District Chengdu 610500, SiChuan, China (e-mail: )
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Famurewa AC, Mukherjee AG, Wanjari UR, Sukumar A, Murali R, Renu K, Vellingiri B, Dey A, Valsala Gopalakrishnan A. Repurposing FDA-approved drugs against the toxicity of platinum-based anticancer drugs. Life Sci 2022; 305:120789. [PMID: 35817170 DOI: 10.1016/j.lfs.2022.120789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/02/2022] [Accepted: 07/05/2022] [Indexed: 11/17/2022]
Abstract
Platinum-based anticancer drugs (PADs), mainly cisplatin, carboplatin, and oxaliplatin, are widely used efficacious long-standing anticancer agents for treating several cancer types. However, clinicians worry about PAD chemotherapy and its induction of severe non-targeted organ toxicity. Compelling evidence has shown that toxicity of PAD on delicate body organs is associated with free radical generation, DNA impairment, endocrine and mitochondrial dysfunctions, oxidative inflammation, apoptosis, endoplasmic reticulum stress, and activation of regulator signaling proteins, cell cycle arrest, apoptosis, and pathways. The emerging trend is the repurposing of FDA-approved non-anticancer drugs (FNDs) for combating the side effects toxicity of PADs. Thus, this review chronicled the mechanistic preventive and therapeutic effects of FNDs against PAD organ toxicity in preclinical studies. FNDs are potential clinical drugs for the modulation of toxicity complications associated with PAD chemotherapy. Therefore, FNDs may be suggested as non-natural agent inhibitors of unpalatable side effects of PADs.
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Affiliation(s)
- Ademola C Famurewa
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, College of Medicine, Alex Ekwueme Federal University, Ndufu-Alike lkwo, Nigeria.
| | - Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India
| | - Aarthi Sukumar
- Department of Integrative Biology, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India
| | - Reshma Murali
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India
| | - Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, Tamil Nadu, India
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, West Bengal 700073, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu 632014, India.
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Obreshkova D, Ivanova S, Yordanova-Laleva P. Influence of chemical structure and mechanism of hydrolysis on pharmacological activity and toxicological profile of approved platinum drugs. PHARMACIA 2022. [DOI: 10.3897/pharmacia.69.e87494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The problems with platinum complexes are resistance and toxicity of anticancer therapy. The aim of current study is the comparison of the influence of chemical structure and mechanism of hydrolysis on pharmacological activity and toxicological profile of approved in platinum drugs: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, Heptaplatin, Satraplatin. Hydrolysis of Carboplatin and Nedaplatin occurs by double step hydration, to obtain the same active products as with Cisplatin: diaqudiamine-platinum. The similarity in mechanisms of hydrolysis of Oxaliplatin, Lobaplatin Heptaplatin, and Satraplatin is that the first part of the hydrolysis corresponds to the ring-opening and addition of the first water molecule, and in the second step of reaction occur the loss of the ligand and the formation of the di-aquated product by the addition of a second water molecule. Cisplatin, Carboplatin, and Oxaliplatin are nephrotoxic. Cisplatin and Heptaplatin are nephrotoxic. The similar dose-limiting effects of Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, and Satraplatin is myelosuppression.
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Basu P, Averitt DL, Maier C, Basu A. The Effects of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (Nrf2) Activation in Preclinical Models of Peripheral Neuropathic Pain. Antioxidants (Basel) 2022; 11:430. [PMID: 35204312 PMCID: PMC8869199 DOI: 10.3390/antiox11020430] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/13/2022] [Accepted: 02/18/2022] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress, resulting from an imbalance between the formation of damaging free radicals and availability of protective antioxidants, can contribute to peripheral neuropathic pain conditions. Reactive oxygen and nitrogen species, as well as products of the mitochondrial metabolism such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, are common free radicals. Nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a transcription factor encoded by the NFE2L2 gene and is a member of the cap 'n' collar subfamily of basic region leucine zipper transcription factors. Under normal physiological conditions, Nrf2 remains bound to Kelch-like ECH-associated protein 1 in the cytoplasm that ultimately leads to proteasomal degradation. During peripheral neuropathy, Nrf2 can translocate to the nucleus, where it heterodimerizes with muscle aponeurosis fibromatosis proteins and binds to antioxidant response elements (AREs). It is becoming increasingly clear that the Nrf2 interaction with ARE leads to the transcription of several antioxidative enzymes that can ameliorate neuropathy and neuropathic pain in rodent models. Current evidence indicates that the antinociceptive effects of Nrf2 occur via reducing oxidative stress, neuroinflammation, and mitochondrial dysfunction. Here, we will summarize the preclinical evidence supporting the role of Nrf2 signaling pathways and Nrf2 inducers in alleviating peripheral neuropathic pain.
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Affiliation(s)
- Paramita Basu
- Pittsburgh Center for Pain Research and The Pittsburgh Project to End Opioid Misuse, Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Dayna L. Averitt
- Division of Biology, School of the Sciences, Texas Woman’s University, Denton, TX 76204, USA; (D.L.A.); (C.M.)
| | - Camelia Maier
- Division of Biology, School of the Sciences, Texas Woman’s University, Denton, TX 76204, USA; (D.L.A.); (C.M.)
| | - Arpita Basu
- Department of Kinesiology and Nutrition Sciences, School of Integrated Health Sciences, University of Nevada, Las Vegas, NV 89154, USA;
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Mezzanotte JN, Grimm M, Shinde NV, Nolan T, Worthen-Chaudhari L, Williams NO, Lustberg MB. Updates in the Treatment of Chemotherapy-Induced Peripheral Neuropathy. Curr Treat Options Oncol 2022; 23:29-42. [PMID: 35167004 PMCID: PMC9642075 DOI: 10.1007/s11864-021-00926-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2021] [Indexed: 12/16/2022]
Abstract
OPINION STATEMENT Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with treatment with platinum-based agents, taxanes, vinca alkaloids, and other specific agents. The long-term consequences of this condition can result in decreased patient quality of life and can lead to reduced dose intensity, which can negatively impact disease outcomes. There are currently no evidence-based preventative strategies for CIPN and only limited options for treatment. However, there are several strategies that can be utilized to improve patient experience and outcomes as more data are gathered in the prevention and treatment setting. Before treatment, patient education on the potential side effects of chemotherapy is key, and although trials have been limited, recommending exercise and a healthy lifestyle before and while undergoing chemotherapy may provide some overall benefit. In patients who develop painful CIPN, our approach is to offer duloxetine and titrate up to 60 mg daily. Chemotherapy doses may also need to be reduced if intolerable symptoms develop during treatment. Some patients may also try acupuncture and physical therapy to help address their symptoms, although this can be limited by cost, time commitment, and patient motivation. Additionally, data on these modalities are currently limited, as studies are ongoing. Overall, approaching each patient on an individual level and tailoring treatment options for them based on overall physical condition, their disease burden, goals of care and co-morbid health conditions, and willingness to trial different approaches is necessary when addressing CIPN.
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Affiliation(s)
- Jessica N. Mezzanotte
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, 395 W 12th Avenue, Room 334B, Columbus, OH 43210
| | - Michael Grimm
- The Ohio State University Comprehensive Cancer Center, 460 W. 10th Avenue, Columbus, OH 43210
| | - Namrata V. Shinde
- Department of Radiology, The Ohio State University Wexner Medical Center, 395 W 12th Avenue, Columbus, OH 43210
| | - Timiya Nolan
- The Ohio State University College of Nursing, 1585 Neil Avenue, Columbus, OH 43210
| | - Lise Worthen-Chaudhari
- Department of Physical Medicine and Rehabilitation, The Ohio State University Wexner Medical Center, 480 Medical Center Drive, Dodd Hall, Suite 1060, Columbus, OH 43210
| | - Nicole O. Williams
- Department of Medical Oncology, The Ohio State University Wexner Medical Center, 1800 Cannon Drive, 1310K Lincoln Tower, Columbus, OH 43210
| | - Maryam B. Lustberg
- Smilow Cancer Hospital/Yale Cancer Center, 35 Park Street, New Haven, CT 06519
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Manto MU. Cerebellotoxic Agents. HANDBOOK OF THE CEREBELLUM AND CEREBELLAR DISORDERS 2022:2363-2408. [DOI: 10.1007/978-3-030-23810-0_96] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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11
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Parama D, Rana V, Girisa S, Verma E, Daimary UD, Thakur KK, Kumar A, Kunnumakkara AB. The promising potential of piperlongumine as an emerging therapeutics for cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:323-354. [PMID: 36046754 PMCID: PMC9400693 DOI: 10.37349/etat.2021.00049] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/04/2021] [Indexed: 12/24/2022] Open
Abstract
In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 million patients every year. The foremost challenges faced in the treatment of this disease are chemoresistance, adverse effects of the drugs, and the high cost of treatment. Though scientific studies over the past few decades have foreseen and are focusing on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action, many more of these agents are not still explored. Piperlongumine (PL), or piplartine, is one such alkaloid isolated from Piper longum Linn. which is shown to be safe and has significant potential in the prevention and therapy of cancer. Numerous shreds of evidence have established the ability of this alkaloid and its analogs and nanoformulations in modulating various complex molecular pathways such as phosphatidylinositol-3-kinase/protein kinase B /mammalian target of rapamycin, nuclear factor kappa-B, Janus kinases/signal transducer and activator of transcription 3, etc. and inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases, etc. In addition, PL was also shown to inhibit radioresistance and chemoresistance and sensitize the cancer cells to the standard chemotherapeutic agents. Therefore, this compound has high potential as a drug candidate for the prevention and treatment of different cancers. The current review briefly reiterates the anti-cancer properties of PL against different types of cancer, which permits further investigation by conducting clinical studies.
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Affiliation(s)
- Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Elika Verma
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Uzini Devi Daimary
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Krishan Kumar Thakur
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Aviral Kumar
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
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12
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Zhang H, Wu J, Yuan J, Li H, Zhang Y, Wu W, Chen W, Wang C, Meng S, Chen S, Huo M, He Y, Zhang C. Ethaselen synergizes with oxaliplatin in tumor growth inhibition by inducing ROS production and inhibiting TrxR1 activity in gastric cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:260. [PMID: 34412665 PMCID: PMC8375208 DOI: 10.1186/s13046-021-02052-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/07/2021] [Indexed: 12/23/2022]
Abstract
Background Oxaliplatin is one of the most commonly used chemotherapeutic agent for the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Hence, it is of great significance to develop novel therapies to potentiate the anti-tumor effect and reduce the toxicity of oxaliplatin. In our previous study, we demonstrated that ethaselen (BBSKE), an inhibitor of thioredoxin reductase, effectively inhibited the growth of gastric cancer cells and promoted apoptosis in vitro. In the present study, we investigated whether BBSKE can potentiate the anti-tumor effect of oxaliplatin in gastric cancer in vivo and vitro. Methods Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells, organoid and tumor tissues was determined by using the endpoint insulin reduction assay. Western blot was used to analyze the expressions of the indicated proteins. Nude mice xenograft models were used to test the effects of BBSKE and oxaliplatin combinations on gastric cancer cell growth in vivo. In addition, we also used the combined treatment of BBSKE and oxaliplatin in three cases of gastric cancer Patient-Derived organoid (GC-PDO) to detect the anti-tumor effect. Results We found that BBSKE significantly enhanced oxaliplatin-induced growth inhibition in gastric cancer cells by inhibiting TrxR1 activity. Because of the inhibition of TrxR1 activity, BBSKE synergized with oxaliplatin to enhance the production of ROS and activate p38 and JNK signaling pathways which eventually induced apoptosis of gastric cancer cells. In vivo, we also found that BBSKE synergized with oxaliplatin to suppress the gastric cancer tumor growth in xenograft nude mice model, accompanied by the reduced TrxR1 activity. Remarkably, we found that BBSKE attenuated body weight loss evoked by oxaliplatin treatment. We also used three cases of GC-PDO and found that the combined treatment of BBSKE and oxaliplatin dramatically inhibited the growth and viability of GC-PDO with increased ROS level, decreased TrxR1 activity and enhanced apoptosis. Conclusions This study elucidates the underlying mechanisms of synergistic effect of BBSKE and oxaliplatin, and suggests that the combined treatment has potential value in gastric cancer therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02052-z.
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Affiliation(s)
- Haiyong Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China
| | - Jing Wu
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China
| | - Jinqiu Yuan
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China
| | - Huafu Li
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China
| | - Yawei Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China
| | - Wang Wu
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China
| | - Wei Chen
- Department of Pathology, The Seventh Affiliated Hospital, Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Chunming Wang
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China
| | - Sijun Meng
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China
| | - Songyao Chen
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China
| | - Mingyu Huo
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China.
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China. .,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China.
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 518107, Shenzhen, Guangdong, China. .,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China.
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13
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Mogi K, Kamiya I, Makino A, Hirao A, Abe R, Doi Y, Shimizu T, Ando H, Morito K, Takayama K, Ishida T, Nagasawa K. Liposomalization of Oxaliplatin Exacerbates the Non-Liposomal Formulation-Induced Decrease of Sweet Taste Sensitivity in Rats. J Pharm Sci 2021; 110:3937-3945. [PMID: 34246630 DOI: 10.1016/j.xphs.2021.07.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/04/2021] [Accepted: 07/06/2021] [Indexed: 11/15/2022]
Abstract
Here, we investigated whether or not the characteristics of the oxaliplatin-induced sweet taste sensitivity were altered by PEGylated liposomalization of oxaliplatin (liposomal oxaliplatin), which enhances its anticancer efficacy. Liposomal oxaliplatin and oxaliplatin were intravenously and intraperitoneally, respectively, administered to male Sprague-Dawley rats at the total dose of 8 mg/kg. A brief-access test for evaluation of sweet taste sensitivity on day 7 revealed that both liposomal oxaliplatin and oxaliplatin decreased the sensitivity of rats, the degree with the former being greater than in the case of the latter. Liposomalization of oxaliplatin increased the accumulation of platinum in lingual non-epithelial tissues, through which taste nerves passed. The lingual platinum accumulation induced by not only liposomal oxaliplatin but also oxaliplatin was decreased on cooling of the tongue during the administration. In the current study, we revealed that liposomalization of oxaliplatin exacerbated the oxaliplatin-induced decrease of sweet taste sensitivity by increasing the accumulation of platinum/oxaliplatin in lingual non-epithelial tissues. These findings may suggest that reduction of liposomal oxaliplatin distribution to the tongue on cooling during the administration prevents exacerbation of the decrease of sweet taste sensitivity, maintaining the quality of life and chemotherapeutic outcome in patients.
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Affiliation(s)
- Keisuke Mogi
- Department of Environmental Biochemistry, Division of Biological Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, JAPAN
| | - Ikumi Kamiya
- Department of Environmental Biochemistry, Division of Biological Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, JAPAN
| | - Aimi Makino
- Department of Environmental Biochemistry, Division of Biological Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, JAPAN
| | - Ayaka Hirao
- Department of Environmental Biochemistry, Division of Biological Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, JAPAN
| | - Reina Abe
- Department of Environmental Biochemistry, Division of Biological Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, JAPAN
| | - Yusuke Doi
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JAPAN
| | - Taro Shimizu
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JAPAN
| | - Hidenori Ando
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JAPAN
| | - Katsuya Morito
- Department of Environmental Biochemistry, Division of Biological Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, JAPAN
| | - Kentaro Takayama
- Department of Environmental Biochemistry, Division of Biological Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, JAPAN
| | - Tatsuhiro Ishida
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, JAPAN
| | - Kazuki Nagasawa
- Department of Environmental Biochemistry, Division of Biological Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, JAPAN.
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14
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Manto MU. Cerebellotoxic Agents. HANDBOOK OF THE CEREBELLUM AND CEREBELLAR DISORDERS 2021:1-46. [DOI: 10.1007/978-3-319-97911-3_96-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/15/2020] [Indexed: 09/02/2023]
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15
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Zhang X, Chen H, Lu Y, Xu C, Yao W, Xu L, Zhang R, Zhang L, Yao Q. Prevention of oxaliplatin-related neurotoxicity by ω-3 PUFAs: A double-blind randomized study of patients receiving oxaliplatin combined with capecitabine for colon cancer. Medicine (Baltimore) 2020; 99:e23564. [PMID: 33327312 PMCID: PMC7738088 DOI: 10.1097/md.0000000000023564] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Peripheral neurotoxicity (PN) is a frequent side effect of oxaliplatin treatment, and also is its dose-limiting toxicity. Studies have confirmed that ω-3 polyunsaturated fatty acids (ω-3 PUFAs) had a neuroprotective effect. However, the efficacy of ω-3 PUFAs on the prevention of oxaliplatin-related neurotoxicity remains unclear. We assessed the effect of ω-3 PUFAs on the neurotoxicity in colon cancer patients treated by oxaliplatin combined with capecitabine. METHODS In a randomized, double-blind, placebo-controlled study, 179 patients with colon cancer receiving oxaliplatin combined with capecitabine were recruited, and randomly assigned to take ω-3 PUFAs, 640 mg t.i.d during chemotherapy and 1 month after the end of the treatment or placebo. All patients were treated with chemotherapy for 6 treatment cycles. The incidence and severity of PN were evaluated, and the nerve conduction was measured before the onset of chemotherapy and 1 month after treatment. In addition, the quality of life was also accessed using Chinese version of European organization for research and treatment of cancer quality of life questionnaire. RESULTS The incidence of PN in the ω-3 PUFAs group and placebo group was 52.22% and 69.66%, respectively (P = .017). In addition, there was a significant difference in the severity of PN between the 2 groups (P = .017). In terms of motor and sensory nerve conduction, the sensory action potentials amplitude of sural nerve in the ω-3 PUFAs group and placebo group after chemotherapy treatment were (15.01 ± 3.14) and (13.00 ± 3.63) μ V respectively, suggesting there was a significant difference in the 2 groups (P = .000). In addition, the mean score of the global health-status/quality of life was obviously higher in the ω-3 PUFAs group than that in the placebo group. CONCLUSION ω-3 PUFAs seem to reduce the incidence and severity of oxaliplatin-related neurotoxicity, and improve the quality of patients' life, indicating it is expected to be a potential drug for the treatment of oxaliplatin-related neurotoxicity.
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Affiliation(s)
| | | | | | - Chao Xu
- Department of Integrated Traditional Chinese and Western Medicine, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
| | - Wang Yao
- Zhejiang Chinese Medical University
| | - Lu Xu
- Zhejiang Chinese Medical University
| | | | - Liping Zhang
- The First Affiliated Hospital of Zhejiang Chinese Medical University
| | - Qinghua Yao
- Department of Integrated Traditional Chinese and Western Medicine, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
- Key Laboratory of Traditional Chinese Medicine Oncology, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
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16
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Lee JH, Gang J, Yang E, Kim W, Jin YH. Bee Venom Acupuncture Attenuates Oxaliplatin-Induced Neuropathic Pain by Modulating Action Potential Threshold in A-Fiber Dorsal Root Ganglia Neurons. Toxins (Basel) 2020; 12:toxins12120737. [PMID: 33255279 PMCID: PMC7760131 DOI: 10.3390/toxins12120737] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/17/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022] Open
Abstract
Oxaliplatin is a third-generation platinum-based chemotherapeutic drug widely used in colorectal cancer treatment. Although potent against this tumor, it can induce cold and mechanical allodynia even after a single injection. The currently used drugs to attenuate this allodynia can also cause unwanted effects, which limit their use. Bee venom acupuncture (BVA) is widely used in Korean medicine to treat pain. Although the effect of BVA on oxaliplatin-induced neuropathic pain has been addressed in many studies, its action on dorsal root ganglia (DRG) neurons has never been investigated. A single oxaliplatin injection (6 mg/kg, intraperitoneally) induced cold and mechanical allodynia, and BVA (0.1 and 1 mg/kg, subcutaneous, ST36) dose-dependently decreased allodynia in rats. On acutely dissociated lumbar 4-6 DRG neurons, 10 min application of oxaliplatin (100 μM) shifted the voltage-dependence of sodium conductance toward negative membrane potentials in A- but not C-fibers. The resting membrane potential remained unchanged, but the action potential threshold decreased significantly compared to that of the control (p < 0.05). However, 0.1 μg/mL of BVA administration increased the lowered action potential threshold. In conclusion, these results suggest that BVA may attenuate oxaliplatin-induced neuropathic pain by altering the action potential threshold in A-fiber DRG neurons.
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Affiliation(s)
- Ji Hwan Lee
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02453, Korea;
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02453, Korea
| | - Juan Gang
- Department of East-West Medicine, Graduate School, Kyung Hee University, Seoul 02453, Korea;
| | - Eunhee Yang
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul 02453, Korea;
| | - Woojin Kim
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02453, Korea;
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02453, Korea
- Department of East-West Medicine, Graduate School, Kyung Hee University, Seoul 02453, Korea;
- Correspondence: (W.K.); (Y.-H.J.)
| | - Young-Ho Jin
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul 02453, Korea;
- Correspondence: (W.K.); (Y.-H.J.)
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Mesenchymal stem cells reduce the oxaliplatin-induced sensory neuropathy through the reestablishment of redox homeostasis in the spinal cord. Life Sci 2020; 265:118755. [PMID: 33189826 DOI: 10.1016/j.lfs.2020.118755] [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: 07/29/2020] [Revised: 11/02/2020] [Accepted: 11/10/2020] [Indexed: 01/02/2023]
Abstract
AIMS The present study was designed to investigate whether the antinociceptive effect of bone marrow-derived mesenchymal stem/stromal cells (MSC) during oxaliplatin (OXL)-induced sensory neuropathy is related to antioxidant properties. MAIN METHODS Male mice C57BL/6 were submitted to repeated intravenous administration of OXL (1 mg/kg, 9 administrations). After the establishment of sensory neuropathy, mice were treated with a single intravenous administration of MSC (1 × 106), vehicle or gabapentin. Paw mechanical and thermal nociceptive thresholds were evaluated through von Frey filaments and cold plate test, respectively. Motor performance was evaluated in the rota-rod test. Gene expression profile, cytokine levels, and oxidative stress markers in the spinal cord were evaluated by real-time PCR, ELISA and biochemical assays, respectively. KEY FINDINGS OXL-treated mice presented behavioral signs of sensory neuropathy, such as mechanical allodynia and thermal hyperalgesia, which were completely reverted by a single administration of MSC. Repeated oral treatment with gabapentin (70 mg/kg) induced only transient antinociception. The IL-1β and TNF-α spinal levels did not differ between mice with or without sensory neuropathy. MSC increased the levels of anti-inflammatory cytokines, IL-10 and TGF-β, in the spinal cord of neuropathic mice, in addition to increasing the gene expression of antioxidant factors SOD and Nrf-2. Additionally, nitrite and MDA spinal levels were reduced by the MSC treatment. SIGNIFICANCE MSC induce reversion of sensory neuropathy induced by OXL possibly by activation of anti-inflammatory and antioxidant pathways, leading to reestablishment of redox homeostasis in the spinal cord.
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Rahman AA, Stojanovska V, Pilowsky P, Nurgali K. Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats. Pflugers Arch 2020; 473:107-120. [PMID: 33074398 DOI: 10.1007/s00424-020-02480-4] [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] [Received: 11/09/2019] [Revised: 09/18/2020] [Accepted: 10/14/2020] [Indexed: 11/29/2022]
Abstract
Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. Neurotoxicity is one of its major adverse effects that often demands dose limitation. However, the effects of chronic oxaliplatin on the toxicity of the autonomic nervous system regulating cardiorespiratory function and adaptive reflexes are unknown. Male Sprague Dawley rats were treated with intraperitoneal oxaliplatin (3 mg kg-1 per dose) 3 times a week for 14 days. The effects of chronic oxaliplatin treatment on baseline mean arterial pressure (MAP); heart rate (HR); splanchnic sympathetic nerve activity (sSNA); phrenic nerve activity (PNA) and its amplitude (PNamp) and frequency (PNf); and sympathetic reflexes were investigated in anaesthetised, vagotomised and artificially ventilated rats. The same parameters were evaluated after acute oxaliplatin injection, and in the chronic treatment group following a single dose of oxaliplatin. The amount of platinum in the brain was determined with atomic absorption spectrophotometry. Chronic oxaliplatin treatment significantly increased MAP, sSNA and PNf and decreased HR and PNamp, while acute oxaliplatin had no effects. Platinum was accumulated in the brain after chronic oxaliplatin treatment. In the chronic oxaliplatin treatment group, further administration of a single dose of oxaliplatin increased MAP and sSNA. The baroreceptor sensitivity and somatosympathetic reflex were attenuated at rest while the sympathoexcitatory response to hypercapnia was increased in the chronic treatment group. This is the first study to reveal oxaliplatin-induced alterations in the central regulation of cardiovascular and respiratory functions as well as reflexes that may lead to hypertension and breathing disorders which may be mediated via accumulated platinum in the brain.
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Affiliation(s)
- Ahmed A Rahman
- College of Health and Biomedicine, Institute for Health and Sport, Victoria University, Melbourne, Australia.,Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
| | - Vanesa Stojanovska
- College of Health and Biomedicine, Institute for Health and Sport, Victoria University, Melbourne, Australia.,Hudson Institute of Medical Research, Monash Health Translation Precinct, Melbourne, Australia
| | - Paul Pilowsky
- Heart Research Institute, Central Clinical School, The University of Sydney, Sydney, Australia
| | - Kulmira Nurgali
- College of Health and Biomedicine, Institute for Health and Sport, Victoria University, Melbourne, Australia. .,Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia. .,Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, Australia. .,Enteric Neuropathy Lab, Western Centre for Health, Research & Education, Sunshine Hospital, 176 Furlong Road, St Albans, Melbourne, Victoria, 3021, Australia.
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Gersten BK, Fitzgerald TS, Fernandez KA, Cunningham LL. Ototoxicity and Platinum Uptake Following Cyclic Administration of Platinum-Based Chemotherapeutic Agents. J Assoc Res Otolaryngol 2020; 21:303-321. [PMID: 32583132 PMCID: PMC7445222 DOI: 10.1007/s10162-020-00759-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/22/2020] [Indexed: 01/04/2023] Open
Abstract
Cisplatin is a widely used anti-cancer drug used to treat a variety of cancer types. One of the side effects of this life-saving drug is irreversible ototoxicity, resulting in permanent hearing loss in many patients. In order to understand why cisplatin is particularly toxic to the inner ear, we compared the hearing loss and cochlear uptake of cisplatin to that of two related drugs, carboplatin and oxaliplatin. These three drugs are similar in that each contains a core platinum atom; however, carboplatin and oxaliplatin are considered less ototoxic than cisplatin. We delivered these three drugs to mice using a 6-week cyclic drug administration protocol. We performed the experiment twice, once using equimolar concentrations of the drugs and once using concentrations of the drugs more proportional to those used in the clinic. For both concentrations, we detected a significant hearing loss caused by cisplatin and no hearing loss caused by carboplatin or oxaliplatin. Cochlear uptake of each drug was measured using inductively coupled plasma mass spectrometry (ICP-MS) to detect platinum. Cochlear platinum levels were highest in mice treated with cisplatin followed by oxaliplatin, while carboplatin was largely excluded from the cochlea. Even when the drug doses were increased, cochlear platinum remained low in mice treated with oxaliplatin or carboplatin. We also examined drug clearance from the inner ear by measuring platinum levels at 1 h and 24 h after drug administration. Our findings suggest that the reduced cochlear platinum we observed with oxaliplatin and carboplatin were not due to increased clearance of these drugs relative to cisplatin. Taken together, our data indicate that the differential ototoxicity among cisplatin, carboplatin, and oxaliplatin is attributable to differences in cochlear uptake of these three drugs.
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Affiliation(s)
- Benjamin K Gersten
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Tracy S Fitzgerald
- Mouse Auditory Testing Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Katharine A Fernandez
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20814, USA. .,Porter Neuroscience Research Center, 35A Convent Drive, Room 1D-955, Bethesda, MD, 20892, USA.
| | - Lisa L Cunningham
- Section on Sensory Cell Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20814, USA
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Zribi A, Nasr SB, Hamdi S, Ayari J, Fendri S, Balti M, Haddaoui A. Oxaliplatin-induced peripheral neuropathy risk factors and management in Tunisian population. Pan Afr Med J 2020; 35:83. [PMID: 32537086 PMCID: PMC7250193 DOI: 10.11604/pamj.2020.35.83.18357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 02/11/2020] [Indexed: 11/11/2022] Open
Abstract
The most important limits of oxaliplatin treatment is its peripheral neurotoxicity. The aim of our study was to evaluate the oxaliplatin-induced peripheral neuropathy, its impact on treatment and its management. One hundred chemo-naive patients treated with oxaliplatin-based regimen in the medical oncology department of the military hospital of Tunis between 2012 and 2017 were recruited retrospectively. Evaluation of neuropathy was done according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V4). Fifty-six patients were aged more than 60 years. The sex-ratio was 1.56. Twenty-seven patients were overweight, 17 were obese and 56 had a BMI inferior to 25 kg/m2. Two patients were consuming alcohol. Twenty-three patients had diabetes. Sixty-four patients developed chronic peripheral neuropathy because of oxaliplatin (grade 1-2 in 58 cases and grade 3 in 6 cases). Sex, BMI, diabetes and alcohol consumption were not associated with the development of peripheral neuropathy. No association was found between grades of neuropathy and sex, alcohol consumption and diabetes. The median cumulative dose of oxaliplatin that induced neuropathy was 432.4 mg/m2. The most prescribed treatment was gabapentin (81%) and carbamazepine (16.8%). The treatment was not sufficient to stop neuropathy in 82.6% of cases. Dose reduction was done in 64.2% of cases, treatment delay in 10.7% of cases and treatment interruption in 10.7% of cases. We didn't find any association between known risk factors and peripheral neuropathy. The cumulative dose is interesting to define or to predict the timing of neurotoxicity.
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Affiliation(s)
- Aref Zribi
- Faculté de Médecine de Tunis, Department of Medical Oncology, The Military Hospital of Tunis, Universiy of Tunis El Manar, Montfleury, Tunis, Tunisia
| | - Sonia Ben Nasr
- Faculté de Médecine de Tunis, Department of Medical Oncology, The Military Hospital of Tunis, Universiy of Tunis El Manar, Montfleury, Tunis, Tunisia
| | - Syrine Hamdi
- Faculté de Médecine de Tunis, Department of Medical Oncology, The Military Hospital of Tunis, Universiy of Tunis El Manar, Montfleury, Tunis, Tunisia
| | - Jihen Ayari
- Faculté de Médecine de Tunis, Department of Medical Oncology, The Military Hospital of Tunis, Universiy of Tunis El Manar, Montfleury, Tunis, Tunisia
| | - Sana Fendri
- Faculté de Médecine de Tunis, Department of Medical Oncology, The Military Hospital of Tunis, Universiy of Tunis El Manar, Montfleury, Tunis, Tunisia
| | - Mehdi Balti
- Faculté de Médecine de Tunis, Department of Medical Oncology, The Military Hospital of Tunis, Universiy of Tunis El Manar, Montfleury, Tunis, Tunisia
| | - Abderrazek Haddaoui
- Faculté de Médecine de Tunis, Department of Medical Oncology, The Military Hospital of Tunis, Universiy of Tunis El Manar, Montfleury, Tunis, Tunisia
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21
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Makker PGS, White D, Lees JG, Parmar J, Goldstein D, Park SB, Howells J, Moalem-Taylor G. Acute changes in nerve excitability following oxaliplatin treatment in mice. J Neurophysiol 2020; 124:232-244. [PMID: 32519566 DOI: 10.1152/jn.00260.2020] [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] [Indexed: 11/22/2022] Open
Abstract
Oxaliplatin chemotherapy produces acute changes in peripheral nerve excitability in humans by modulating voltage-gated Na+ channel activity. However, there are few animal studies of oxaliplatin-induced neuropathy that demonstrate similar changes in excitability. In the present study, we measured the excitability of motor and sensory caudal nerve in C57BL/6 mice after oxaliplatin injections either systemically (intraperitoneal) or locally (intramuscular at the base of the tail). As opposed to intraperitoneal administration of oxaliplatin, a single intramuscular injection of oxaliplatin produced changes in both motor and sensory axons. In motor axons, oxaliplatin caused a greater change in response to long-lasting depolarization and an upward shift in the recovery cycle, particularly at 24 h [depolarizing threshold electrotonus (TEd) 10-20 ms, P = 0.0095; TEd 90-100 ms, P = 0.0056) and 48 h (TEd 10-20 ms, P = 0.02; TEd 90-100 ms, P = 0.04) posttreatment. Oxaliplatin treatment also stimulated the production of afterdischarges in motor axons. These changes were transient and showed dose dependence. Mathematical modeling demonstrated that these changes could be accounted for by slowing inactivation of voltage-gated Na+ channels by 73.3% and reducing fast K+ conductance by 47% in motor axons. In sensory axons, oxaliplatin caused an increase in threshold, a reduction in peak amplitude, and greater threshold changes to strong hyperpolarizing currents on days 4 and 8. Thus, local administration of oxaliplatin produced clinically relevant changes in nerve excitability in mice and may provide an alternative approach for the study of acute oxaliplatin-induced neurotoxicity.NEW & NOTEWORTHY We present a novel mouse model of acute oxaliplatin-induced peripheral neurotoxicity that is comparable to clinical observations. Intramuscular injection of oxaliplatin produced acute changes in motor nerve excitability that were attributable to alterations in Na+ and K+ channel activity. Conversely, we were unable to show any significant changes in nerve excitability with systemic intraperitoneal injections of oxaliplatin. This study suggests that local intramuscular injection is a valid approach for modelling oxaliplatin-induced peripheral neuropathy in animals.
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Affiliation(s)
- Preet G S Makker
- Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales, Australia
| | - Daniel White
- Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales, Australia
| | - Justin G Lees
- Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales, Australia
| | - Jasneet Parmar
- Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales, Australia
| | - David Goldstein
- Department of Medical Oncology, Prince of Wales Hospital, Randwick, New South Wales, Australia.,Prince of Wales Clinical School, UNSW, New South Wales, Australia
| | - Susanna B Park
- Brain and Mind Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - James Howells
- Central Clinical School, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
| | - Gila Moalem-Taylor
- Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales (UNSW), Sydney, New South Wales, Australia
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22
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Effect of Oxaliplatin on Voltage-Gated Sodium Channels in Peripheral Neuropathic Pain. Processes (Basel) 2020. [DOI: 10.3390/pr8060680] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Oxaliplatin is a chemotherapeutic drug widely used to treat various types of tumors. However, it can induce a serious peripheral neuropathy characterized by cold and mechanical allodynia that can even disrupt the treatment schedule. Since the approval of the agent, many laboratories, including ours, have focused their research on finding a drug or method to decrease this side effect. However, to date no drug that can effectively reduce the pain without causing any adverse events has been developed, and the mechanism of the action of oxaliplatin is not clearly understood. On the dorsal root ganglia (DRG) sensory neurons, oxaliplatin is reported to modify their functions, such as the propagation of the action potential and induction of neuropathic pain. Voltage-gated sodium channels in the DRG neurons are important, as they play a major role in the excitability of the cell by initiating the action potential. Thus, in this small review, eight studies that investigated the effect of oxaliplatin on sodium channels of peripheral neurons have been included. Its effects on the duration of the action potential, peak of the sodium current, voltage–response relationship, inactivation current, and sensitivity to tetrodotoxin (TTX) are discussed.
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23
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Management of Oxaliplatin-Induced Peripheral Sensory Neuropathy. Cancers (Basel) 2020; 12:cancers12061370. [PMID: 32471028 PMCID: PMC7352541 DOI: 10.3390/cancers12061370] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/18/2020] [Accepted: 05/23/2020] [Indexed: 12/11/2022] Open
Abstract
Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment affecting the majority of oxaliplatin-treated patients, mostly with the onset of acute symptoms, but also with the establishment of a chronic sensory loss that is supposed to be due to dorsal root ganglia neuron damage. The pathogenesis of acute as well as chronic OIPN is still not completely known, and this is a limitation in the identification of effective strategies to prevent or limit their occurrence. Despite intense investigation at the preclinical and clinical levels, no treatment can be suggested for the prevention of OIPN, and only limited evidence for the efficacy of duloxetine in the treatment setting has been provided. In this review, ongoing neuroprotection clinical trials in oxaliplatin-treated patients will be analyzed with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the therapeutic approach. It can be concluded that (1) prevention and treatment of OIPN still remains an important and unmet clinical need, (2) further, high-quality research is mandatory in order to achieve reliable and effective results, and (3) dose and schedule modification of OHP-based chemotherapy is currently the most effective approach to limit the severity of OIPN.
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24
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Vitale MG, Barbato C, Crispo A, Habetswallner F, De Martino BM, Riccardi F, Maione A, Eisenwagen S, Vitale G, Cartenì G. ZeOxaNMulti Trial: A Randomized, Double-Blinded, Placebo-Controlled Trial of Oral PMA-zeolite to prevent Chemotherapy-Induced Side Effects, in particular, Peripheral Neuropathy. Molecules 2020; 25:molecules25102297. [PMID: 32414185 PMCID: PMC7288011 DOI: 10.3390/molecules25102297] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/09/2020] [Accepted: 05/11/2020] [Indexed: 01/22/2023] Open
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is the most frequently reported adverse effect of oxaliplatin. In this study, we set out to evaluate the role of the panaceo-micro-activation (PMA) zeolite in the reduction of the incidence of CIPN and hematological and liver toxicity. The possible impact of the PMA-zeolite as an adjuvant therapeutic agent is based on its detoxification properties toward agents promoting the development of neuropathy (e.g., ammonium—recognized as a neurotoxic agent produced by tumors), as well as its positive impact on immunity and oxidative stress through its effects in the gastrointestinal tract. From April 2015 to October 2018, a total of 120 patients (pts) diagnosed with predominantly colorectal cancer requiring oxaliplatin-based chemotherapy were randomized to receive either the PMA-zeolite (Multizeo Med) or placebo while undergoing oxaliplatin-based chemotherapy. A nerve-conduction study (NCS) was planned at the baseline, after three and six months of chemotherapy, to evaluate CIPN. Furthermore, the evaluation of hematological and liver toxicity was performed during every cycle of chemotherapy. 70.6% and 64.3% of patients developed CIPN in the placebo and the PMA-zeolite group, respectively. Patients treated with the PMA-zeolite were able to undergo more cycles of chemotherapy (p = 0.03), which also indicates a significant improvement in tolerance to the therapy. The group treated with the PMA-zeolite showed a lower CIPN (although not statistically significant within the whole group of subjects) compared to patients receiving placebo. This advantage was, however, statistically significant in men (p = 0.047). In addition, supplementation with the PMA-zeolite resulted in a lower incidence of severe-grade hematological toxicity (trend toward statistical significance of p = 0.09 was observed). Cancer patients may benefit from the therapy with the appropriate certified zeolite-products (e.g., the PMA-zeolite) for human use in CIPN. The lower CIPN (statistically significant results in the male subgroup) was accompanied by a trend of lower incidence of severe-grade hematological toxicity. Furthermore, these benefits led to a better tolerance toward chemotherapy (increase in cycles) and allow an improved compliance with the oncological treatment protocol.
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Affiliation(s)
- Maria Giuseppa Vitale
- Medical Oncology Unit, University Hospital of Modena, 41125 Modena, Italy
- Correspondence:
| | - Carmela Barbato
- Medical Oncology Unit, AORN Antonio Cardarelli, 80131 Naples, Italy; (C.B.); (F.R.); (A.M.); (G.C.)
| | - Anna Crispo
- Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori-IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy;
| | | | | | - Ferdinando Riccardi
- Medical Oncology Unit, AORN Antonio Cardarelli, 80131 Naples, Italy; (C.B.); (F.R.); (A.M.); (G.C.)
| | - Angela Maione
- Medical Oncology Unit, AORN Antonio Cardarelli, 80131 Naples, Italy; (C.B.); (F.R.); (A.M.); (G.C.)
| | | | - Giovanna Vitale
- School of Medicine and Surgery, University of Campania Luigi Vanvitelli, 81100 Caserta, Italy;
| | - Giacomo Cartenì
- Medical Oncology Unit, AORN Antonio Cardarelli, 80131 Naples, Italy; (C.B.); (F.R.); (A.M.); (G.C.)
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25
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van Haren F, van den Heuvel S, Radema S, van Erp N, van den Bersselaar L, Vissers K, Steegers M. Intravenous lidocaine affects oxaliplatin pharmacokinetics in simultaneous infusion. J Oncol Pharm Pract 2020; 26:1850-1856. [PMID: 32075507 DOI: 10.1177/1078155220905011] [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: 11/17/2022]
Abstract
BACKGROUND Oxaliplatin is a chemotherapeutic agent used to treat malignancies of the gastrointestinal tract. Neuropathy is a frequent dose-limiting side-effect of oxaliplatin therapy, without preventive or curative strategies. Concomitant administration of intravenous lidocaine could be a promising treatment. However, the effect of intravenous lidocaine on oxaliplatin pharmacokinetics was never studied before. We evaluated the effect of lidocaine on the area under the curve and Cmax of oxaliplatin as a part of a larger study addressing the prevention and treatment of oxaliplatin induced peripheral neuropathy with lidocaine. METHODS In this prospective cross-over trial, patients received an oxaliplatin cycle with and without lidocaine (bolus 1.5 mg kg-1 followed by 1.5 mg kg-1 h-1 in 3 h). Levels of oxaliplatin, measured as ultrafiltrable platinum were determined at 10 min after cessation of oxaliplatin infusion and hourly thereafter. Outcomes are the difference in area under the curve of oxaliplatin (primary) and the difference in the Cmax of oxaliplatin (secondary). RESULTS No difference in the %Δ area under the curve of oxaliplatin (-2.40 ± 7.66, 90% CI +10.50 to -15.31) was found. However, %Δ Cmax of oxaliplatin (-28.72 ± 6.01, 90% CI -18.59 to -38.85) was lower to a statistically significant extent in the chemotherapy cycle with lidocaine. No (serious) adverse events were reported. CONCLUSIONS Lidocaine does not affect the area under the curve of oxaliplatin, which is the most important parameter in drug interaction studies and for oxaliplatin treatment effect. The lower Cmax in the chemotherapeutic cycle with lidocaine is significant and remarkable, but with an unknown exact mechanism or clinical significance, making further research desirable.
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Affiliation(s)
- Frank van Haren
- Department of Anesthesiology Pain and Palliative Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Sandra van den Heuvel
- Department of Anesthesiology Pain and Palliative Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Sandra Radema
- Department of Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Nielka van Erp
- Department of Pharmacology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Luuk van den Bersselaar
- Department of Anesthesiology Pain and Palliative Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Kris Vissers
- Department of Anesthesiology Pain and Palliative Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Monique Steegers
- Department of Anesthesiology Pain and Palliative Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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26
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Kaiser K, Lyleroehr M, Shaunfield S, Lacson L, Corona M, Kircher S, Nittve M, Cella D. Neuropathy experienced by colorectal cancer patients receiving oxaliplatin: A qualitative study to validate the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scale. World J Gastrointest Oncol 2020; 12:205-218. [PMID: 32104551 PMCID: PMC7031152 DOI: 10.4251/wjgo.v12.i2.205] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/29/2019] [Accepted: 01/06/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Although oxaliplatin is widely established as a standard treatment in colorectal cancer (CRC), oxaliplatin-induced neuropathy has emerged as a prominent dose-limiting side effect associated with quality of life decrements. Ongoing monitoring and management of neuropathy is important for CRC patient quality of life and adherence to treatment. Therefore, a validated self-reported measure of neuropathy would aid in the management and assessment of oxaliplatin-induced neuropathy in clinical practice and research. We sought to evaluate the content validity of the 13-item Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity subscale (FACT/GOG-Ntx) for CRC patients receiving oxaliplatin. AIM To understand the neuropathy experiences of CRC patients and assess content validity of the FACT/GOG-Ntx. METHODS Semi-structured concept elicitation and cognitive debriefing interviews were conducted with 31 CRC patients experiencing peripheral neuropathy from current or previous oxaliplatin treatment. Interview data were analyzed using a constant comparative approach, and data were mapped to the FACT/GOG-Ntx to assess content validity. RESULTS Mean age of the sample was 54 (range 34-82). The sample was primarily Caucasian (84%) and consisted of nearly equal numbers of men and women. Participants described 28 unique neuropathy symptoms; hand tingling (experienced by 87% of respondents); feet tingling (81%); hand numbness (68%); and feet numbness (84%) were most frequently mentioned. Neuropathy symptoms occurring on the feet were most often identified as most bothersome by participants. Eleven of the 13 FACT/GOG-Ntx items exhibited moderate to strong evidence of content validity. Two items related to trouble hearing and ringing in the ears had weak support; however, these items represent severe neuropathy and could be useful for a patient reported outcome measure. CONCLUSION The FACT/GOG-Ntx represents the key neuropathy experiences of CRC patients treated with oxaliplatin.
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Affiliation(s)
- Karen Kaiser
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Madison Lyleroehr
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Sara Shaunfield
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Leilani Lacson
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Maria Corona
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Sheetal Kircher
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Malin Nittve
- Project and Regulatory Affairs, PledPharma AB, Stockholm 114 46, Sweden
| | - David Cella
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
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27
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Zhang P, Shi L, Zhang T, Hong L, He W, Cao P, Shen X, Zheng P, Xia Y, Zou P. Piperlongumine potentiates the antitumor efficacy of oxaliplatin through ROS induction in gastric cancer cells. Cell Oncol (Dordr) 2019; 42:847-860. [PMID: 31493144 DOI: 10.1007/s13402-019-00471-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2019] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Oxaliplatin is one of the most commonly used chemotherapeutic agents in the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Therefore, there is a pressing need to develop novel therapies to potentiate the efficacy and reduce the toxicity of oxaliplatin. Piperlongumine (PL), an alkaloid isolated from Piper longum L., has recently been identified as a potent agent against cancer cells in vitro and in vivo. In the present study, we investigated whether PL can potentiate the antitumor effect of oxaliplatin in gastric cancer cells. METHODS Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells or tumor tissues was determined using an endpoint insulin reduction assay. Western blotting was used to analyze the expression levels of the indicated proteins. Nude mice xenograft models were used to test the effects of PL and oxaliplatin combinations on gastric cancer cell growth in vivo. RESULTS We found that PL significantly enhanced oxaliplatin-induced growth inhibition in both gastric and colon cancer cells. Moreover, we found that PL potentiated the antitumor effect of oxaliplatin by inhibiting TrxR1 activity. PL combined with oxaliplatin markedly suppressed the activity of TrxR1, resulting in the accumulation of ROS and, thereby, DNA damage induction and p38 and JNK signaling pathway activation. Pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly abrogated the combined treatment-induced ROS generation, DNA damage and apoptosis. Importantly, we found that activation of the p38 and JNK signaling pathways prompted by PL and oxaliplatin was also reversed by NAC pretreatment. In vivo, we found that PL combined with oxaliplatin significantly suppressed tumor growth in a gastric cancer xenograft model, and effectively reduced the activity of TrxR1 in tumor tissues. Remarkably, we found that PL attenuated body weight loss evoked by oxaliplatin treatment. CONCLUSIONS Our data support a synergistic effect of PL and oxaliplatin and suggest that application of its combination may be more effective for the treatment of gastric cancer than oxaliplatin alone.
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Affiliation(s)
- Peichen Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Lingyan Shi
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Tingting Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Lin Hong
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Wei He
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Peihai Cao
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xin Shen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Peisen Zheng
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yiqun Xia
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
| | - Peng Zou
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
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28
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Falsini M, Catarzi D, Varano F, Ceni C, Dal Ben D, Marucci G, Buccioni M, Volpini R, Di Cesare Mannelli L, Lucarini E, Ghelardini C, Bartolucci G, Menicatti M, Colotta V. Antioxidant-Conjugated 1,2,4-Triazolo[4,3- a]pyrazin-3-one Derivatives: Highly Potent and Selective Human A 2A Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain. J Med Chem 2019; 62:8511-8531. [PMID: 31453698 DOI: 10.1021/acs.jmedchem.9b00778] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
New 8-amino-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-ones were designed to obtain dual antioxidant-human A2A adenosine receptor (hA2A AR) antagonists. Two sets of compounds were synthesized, the first featuring phenol rings at the 6-position, the second bearing the lipoyl and 4-hydroxy-3,5-di-tertbut-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines (1-21) were potent and selective hA2A AR antagonists (Ki = 0.17-54.5 nM). Compounds 11, 15, and 21, featuring antioxidant moieties, and compound 12, lacking the antioxidant functionality, reduced oxaliplatin-induced toxicity in microglia cells, the most active being the lipoyl-derivative 15 and the (4-hydroxy-3,5-di-tert-butyl)benzoyl-analogue 21 which were effective in reducing the oxygen free radical level. The lipoyl-derivative 15 was also able to revert oxaliplatin-induced neuropathy in the mouse. In vivo efficacy of 15 makes it a promising neuroprotective agent in oxidative stress-related diseases.
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Affiliation(s)
- Matteo Falsini
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy
| | - Daniela Catarzi
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy
| | - Flavia Varano
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy
| | - Costanza Ceni
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy
| | - Diego Dal Ben
- Scuola di Scienze del Farmaco e dei Prodotti della Salute , Università degli Studi di Camerino , Via S. Agostino 1 , 62032 Camerino , Macerata , Italy
| | - Gabriella Marucci
- Scuola di Scienze del Farmaco e dei Prodotti della Salute , Università degli Studi di Camerino , Via S. Agostino 1 , 62032 Camerino , Macerata , Italy
| | - Michela Buccioni
- Scuola di Scienze del Farmaco e dei Prodotti della Salute , Università degli Studi di Camerino , Via S. Agostino 1 , 62032 Camerino , Macerata , Italy
| | - Rosaria Volpini
- Scuola di Scienze del Farmaco e dei Prodotti della Salute , Università degli Studi di Camerino , Via S. Agostino 1 , 62032 Camerino , Macerata , Italy
| | - Lorenzo Di Cesare Mannelli
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia , Università degli Studi di Firenze , Viale Pieraccini 6 , 50139 Firenze , Italy
| | - Elena Lucarini
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia , Università degli Studi di Firenze , Viale Pieraccini 6 , 50139 Firenze , Italy
| | - Carla Ghelardini
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia , Università degli Studi di Firenze , Viale Pieraccini 6 , 50139 Firenze , Italy
| | - Gianluca Bartolucci
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy
| | - Marta Menicatti
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy
| | - Vittoria Colotta
- Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy
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Krøigård T, Metaxas A, Wirenfeldt M, Finsen B. Protective effect of ibuprofen in a rat model of chronic oxaliplatin-induced peripheral neuropathy. Exp Brain Res 2019; 237:2645-2651. [PMID: 31388734 DOI: 10.1007/s00221-019-05615-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 07/26/2019] [Indexed: 12/31/2022]
Abstract
Despite extensive preclinical and clinical investigations, a clinically relevant neuroprotective agent against oxaliplatin-induced peripheral neuropathy, which affects the quality of life following chemotherapy, has not been identified. Epidemiological data suggest that ibuprofen may reduce the risk of neuropathy. Male rats were treated with oxaliplatin (n = 6), oxaliplatin and ibuprofen (n = 5) or vehicle (n = 5) every second day for 15 days. Neuropathy was evaluated using mechanical detection thresholds (MDT) at the hind paw and sensory nerve conduction velocity (SNCV) in the tail nerve at baseline, right after and 3 weeks after the end of treatment. Intraepidermal nerve fibre density (IENFD) was evaluated in the hind paw and inflammation in the dorsal root ganglia 3 weeks after treatment. Inflammation in the dorsal root ganglia was assessed using quantitative real-time RT-PCR (qPCR) of the mRNA levels for the pro-inflammatory cytokines, TNF-α and IL-1β, and by immunohistochemical staining for Iba1+ macrophages. SNCV was reduced in rats treated with oxaliplatin and with oxaliplatin and ibuprofen compared to control rats 3 weeks after treatment. No differences were found for MDT 3 weeks after treatment. IENFD was reduced in rats treated with oxaliplatin. There was a trend towards up-regulation of TNF-α mRNA levels in rats treated with oxaliplatin and with oxaliplatin and ibuprofen. Morphological changes of Iba1+ macrophages suggested activation, but no differences were found in area fraction or size of macrophage cell bodies. The results did not support a neuroprotective effect of ibuprofen but indicated that inflammation may play a role in oxaliplatin-induced peripheral neuropathy.
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Affiliation(s)
- Thomas Krøigård
- Department of Neurology, Odense University Hospital, Odense, Denmark. .,Institute of Clinical Research, University of Southern Denmark, J. B. Winsløws Vej 4, 5000, Odense C, Denmark.
| | - Athanasios Metaxas
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Martin Wirenfeldt
- Department of Pathology, Odense University Hospital, Odense, Denmark.,Institute of Clinical Research, University of Southern Denmark, J. B. Winsløws Vej 4, 5000, Odense C, Denmark
| | - Bente Finsen
- Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
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Cao P, Xia Y, He W, Zhang T, Hong L, Zheng P, Shen X, Liang G, Cui R, Zou P. Enhancement of oxaliplatin-induced colon cancer cell apoptosis by alantolactone, a natural product inducer of ROS. Int J Biol Sci 2019; 15:1676-1684. [PMID: 31360110 PMCID: PMC6643222 DOI: 10.7150/ijbs.35265] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 05/11/2019] [Indexed: 12/23/2022] Open
Abstract
Colon cancer is a malignant type of cancer with high prevalence and is one of the primary causes of cancer-related deaths. Oxaliplatin plays a significant role in the treatment of cancer, but the application of oxaliplatin is restricted due to its toxic side effects and drug resistance in clinical practice. Therefore, there is an urgent need for new strategies that can synergize with oxaliplatin for confronting colon cancer. Alantolactone (ALT), a natural sesquiterpene lactone, possesses antitumor properties in a number of cancer cell lines. In the present study, we investigated how ALT acts synergistically with oxaliplatin on human colorectal cancer HCT116 and RKO cells in vitro and in vivo. We observed that ALT strengthened the effect of oxaliplatin-induced growth restrain and apoptosis in HCT116 and RKO cells. It is through a mechanism concerning remarkable accumulation of intracellular reactive oxygen species (ROS) and activation of JNK and p38 MAPK signaling pathways. These changes ultimately induced apoptosis of HCT116 and RKO cells. Pretreatment of cells with the ROS reversal agent NAC significantly blocked the apoptosis induced by the combination treatment, and suppressed expression of JNK and p38 phosphorylation in HCT116 and RKO cells. In the xenograft model, the combination therapy displayed stronger antitumor activity compared with single agents. Immunohistochemistry of subsequent treatment tumors showed a significant decrease in proliferation as compared to either of the treatments alone. These results suggest that the combination treatment with ALT and oxaliplatin may become a potential therapeutic strategy for colon cancer.
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Affiliation(s)
- Peihai Cao
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yiqun Xia
- Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wei He
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Tingting Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Lin Hong
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Peisen Zheng
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xin Shen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ri Cui
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Peng Zou
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
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31
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Singh AK, Chandra R. Pollutants released from the pulp paper industry: Aquatic toxicity and their health hazards. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2019; 211:202-216. [PMID: 31029991 DOI: 10.1016/j.aquatox.2019.04.007] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 03/11/2019] [Accepted: 04/09/2019] [Indexed: 06/09/2023]
Abstract
The pulp paper industries release wastewater containing very complex organic and inorganic pollutants. These pollutants are discharged mainly pulping and bleaching process during paper manufacturing. The main gaseous pollutants hydrogen sulfides, sodium sulfide, methyl mercaptan, sulfur, and chlorine dioxide is reported for chronic, respiratory disorder and irritation to skin, eyes and cardiac problem along with nausea and headache. The major inorganic pollutants include ferrous, copper, zinc, nickel, and magnesium, which is reported for neurotoxicity, toxic to juvenile channel catfish (Ictalurus punctatus) and Accumulation to gill > liver > ovary > muscle. The detected major organic and inorganic pollutants are hexadecanoic acids, octacosane, β-sitosterol trimethylsilyl ether, 1-tetradecane, 2-methoxy phenol, trichlorocatechol, tetrachlorocatechol, chlorophenols, chloroguaiacols, chlorosyringols, chlorocatechols, terpenes, methanol, phenol, alkylated phenols, decalone, benzoic acid, abietic acid, and dehydroabietic acid. Several of these compounds are reported as endocrine-disrupting chemicals (EDCs). Therefore, direct toxicity of effluent to the reproductive system in aquatic flora and fauna are reported. Several reports have highlighted reduced gonad size, change in secondary sexual character, delayed maturity and suppression of sex hormone in fish rainbow trout (Oncorhynchus mykiss) and mosquitofish (Gambusia holbrooki) further the in-vitro studies of organic compounds on fish, Salmonella typhimurium, Vibrio fischeri, and Saccharomyces have shown inhibition in growth and luminescence properties. The presence of organic and inorganic pollutants in pulp paper industry wastewater causes phytotoxicity chromosomal aberration in Allium cepa. Thus the manuscript has concluded that detected pollutants produced foul odors and cause hermaphroditism in fish, hepatotoxicity and mutagenic effect. In addition, the growth of coliform bacteria in River and other aquatic resources has been reported due to contamination of PPI effluent. The studies also highlighted the presence of tannins, chlorophenols, dioxins, furans, biocide, fatty acids, and resin acids along with chlorolignine compounds as persistent organic pollutants (POP), which needs special attention for pollution prevention of rivers, lakes and other aquatic resources.
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Affiliation(s)
- Ajay Kumar Singh
- Department of Environmental Microbiology, School of Environmental Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar Raibareli Road, Lucknow 226025, India
| | - Ram Chandra
- Department of Environmental Microbiology, School of Environmental Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar Raibareli Road, Lucknow 226025, India.
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32
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Chemokine CCL2 and its receptor CCR2 in the dorsal root ganglion contribute to oxaliplatin-induced mechanical hypersensitivity. Pain 2019; 159:1308-1316. [PMID: 29554018 DOI: 10.1097/j.pain.0000000000001212] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Activation of innate immune mechanisms within the dorsal root ganglion and spinal dorsal horn has been shown to play a key role in the development of neuropathic pain including paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Here, we tested whether similar mechanisms are generalizable to oxaliplatin-induced CIPN. After a single intraperitoneal injection of 3 mg/kg oxaliplatin, mechanical withdrawal threshold and the expression of C-C chemokine ligand 2 (CCL2) and its receptor, CCR2, in the dorsal root ganglion were measured by behavioral testing and immunohistochemical staining, respectively. Mechanical responsiveness increased from the first day after oxaliplatin injection and persisted until day 15, the last day of this experiment. Immunohistochemical showed that the expression of CCL2/CCR2 started to increase by 4 hours after oxaliplatin treatment, was significantly increased at day 4, and then both signals became normalized by day 15. Cotreatment with intrathecal anti-CCL2 antibodies prevented the development of oxaliplatin-induced mechanical hyperresponsiveness, and transiently reversed established hyperalgesia when given 1 week after chemotherapy. This is the first study to demonstrate CCL2/CCR2 signaling in a model of oxaliplatin-related CIPN; and it further shows that blocking of this signal can attenuate the development of oxaliplatin-induced mechanical hyperalgesia. Activation of innate immune mechanisms may therefore be a generalized basis for CIPN irrespective of the specific class of agent.
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Chen D, Zhao J, Cong W. Chinese Herbal Medicines Facilitate the Control of Chemotherapy-Induced Side Effects in Colorectal Cancer: Progress and Perspective. Front Pharmacol 2018; 9:1442. [PMID: 30581388 PMCID: PMC6294045 DOI: 10.3389/fphar.2018.01442] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 11/22/2018] [Indexed: 12/24/2022] Open
Abstract
Side effects, including nausea, vomiting, mucositis, peripheral neuropathy, and diarrhea, have been frequently reported in colorectal cancer (CRC) patients undergoing chemotherapy. Chinese Herbal Medicines (CHMs) display distinct clinical outcomes, as a result, they have been increasingly used as an adjuvant therapy to manage chemotherapy-induced side effects. In this review, we aim to intensively explore the molecular mechanisms of CHMs, underline the significance of CHMs in mitigating the side effects induced by chemotherapy, and examine the necessary studies required to understand the role of CHMs in alleviating chemotherapy-induced side effects. Specifically, ginger, Astragali Radix, and Liujunzi Decoction have been verified to ameliorate nausea and vomiting. Banxia Xiexin Decoction and Huangqin Decoction have been confirmed to be beneficial to mucositis and delayed-onset of diarrhea. Moreover, Niuche Shenqi Wan, Guilong Tongluo Decoction, Huangqi Guizhi Wuwu Decoction, and tumeric have been found to display potential therapeutic effects for preventing the genesis and development of peripheral neurotoxicity. These findings have further emphasized the pivotal role of CHMs in improving the outcomes of chemotherapy-induced side effects in CRC. Nonetheless, more molecular evidence is required to comprehensively understand and more appropriately apply CHMs in routine clinical practice for CRC.
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Affiliation(s)
- Dongmei Chen
- Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.,Graduate School, Beijing University of Chinese Medicine, Beijing, China.,The University of Texas, MD Anderson Cancer Center, Houston, TX, United States
| | - Jun Zhao
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Weihong Cong
- Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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Fujita S, Hirota T, Sakiyama R, Baba M, Ieiri I. Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy. J Neurochem 2018; 148:373-385. [PMID: 30295925 DOI: 10.1111/jnc.14607] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 06/19/2018] [Accepted: 10/01/2018] [Indexed: 12/23/2022]
Abstract
Oxaliplatin is widely used as a key drug in the treatment of colorectal cancer. However, its administration is associated with the dose-limiting adverse effect, peripheral neuropathy. Platinum accumulation in the dorsal root ganglion (DRG) is the major mechanism responsible for oxaliplatin-induced neuropathy. Some drug transporters have been identified as platinum complex transporters in kidney or tumor cells, but not yet in DRG. In the present study, we investigated oxaliplatin transporters and their contribution to peripheral neuropathy. We identified 12 platinum transporters expressed in DRG with real-time PCR, and their transiently overexpressing cells were established. After exposure to oxaliplatin, the accumulation of platinum in these overexpressing cells was evaluated using a coupled plasma mass spectrometer. Octn1/2- and Mate1-expressing cells showed the intracellular accumulation of oxaliplatin. In an animal study, peripheral neuropathy developed after the administration of oxaliplatin (4 mg/kg, intravenously, twice a week) to siRNA-injected rats (0.5 nmol, intrathecally, once a week) was demonstrated with the von Frey test. The knockdown of Octn1 in DRG ameliorated peripheral neuropathy, and decreased platinum accumulation in DRG, whereas the knockdown of Octn2 did not. Mate1 siRNA-injected rats developed more severe neuropathy than control rats. These results indicate that Octn1 and Mate1 are involved in platinum accumulation at DRG and oxaliplatin-induced peripheral neuropathy.
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Affiliation(s)
- Shunsuke Fujita
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Hirota
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryo Sakiyama
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Misaki Baba
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Ichiro Ieiri
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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35
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36
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Di Cesare Mannelli L, Piccolo M, Maione F, Ferraro MG, Irace C, De Feo V, Ghelardini C, Mascolo N. Tanshinones from Salvia miltiorrhiza Bunge revert chemotherapy-induced neuropathic pain and reduce glioblastoma cells malignancy. Biomed Pharmacother 2018; 105:1042-1049. [DOI: 10.1016/j.biopha.2018.06.047] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 06/12/2018] [Accepted: 06/12/2018] [Indexed: 12/28/2022] Open
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37
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Tabata A, Kanai M, Horimatsu T, Tsuboyama T, Matsushima K, Kato T. Changes in upper extremity function, ADL, and HRQoL in colorectal cancer patients after the first chemotherapy cycle with oxaliplatin: a prospective single-center observational study. Support Care Cancer 2018; 26:2397-2405. [PMID: 29423680 PMCID: PMC5982431 DOI: 10.1007/s00520-018-4070-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 01/22/2018] [Indexed: 12/27/2022]
Abstract
PURPOSE Oxaliplatin, an important chemotherapeutic agent in colorectal cancer, causes chemotherapy-induced peripheral neuropathy (CIPN), for which prophylactic or therapeutic interventions are lacking. We aimed to investigate changes in upper extremities, activities of daily living (ADL), and health-related quality of life (HRQoL) parameters after the first chemotherapy cycle. METHODS Thirty-eight colorectal cancer patients scheduled to receive the leucovorin, 5'-fluorouracil, oxaliplatin (FOLFOX) therapy or the capecitabine, oxaliplatin (CAPOX) therapy, participated. Patients underwent objective assessment of sensory function, muscular strength, and manual dexterity and answered the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the Disabilities of the Arm, Shoulder, and Hand-Disability/Symptom (DASH-DS) questionnaires for subjective assessment. The CIPN was assessed at baseline and prior to the second drug cycle. RESULTS Light touch sensation in both hands worsened significantly after the first drug cycle, though no significant changes were observed in muscular strength and manual dexterity. The QLQ-C30 analysis showed that Physical Functioning, Role Functioning, Nausea and Vomiting, and Dyspnea were significantly worse, whereas Emotional Functioning was improved. The DASH-DS analysis revealed significant worsening of dysfunction and subjective symptoms. CONCLUSIONS Our results suggest that light touch sensation may worsen even in the absence of multiple chemotherapy cycles. Even if arm and hand function (muscular strength and manual dexterity) is apparently intact, patients may experience dysfunction and decreased HRQoL. For preserving or improving patients' ADL and HRQoL, it is imperative to provide support at chemotherapy initiation.
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Affiliation(s)
- Ami Tabata
- Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, 53, Kawahara-cho, Syogoin, Sakyo-ku, Kyoto City, Kyoto, 606-8507, Japan.
- Rehabilitation Unit, Kyoto University Hospital, 54, Kawahara-cyo, Syogoin, Sakyo-ku, Kyoto City, Kyoto, 606-8507, Japan.
| | - Masashi Kanai
- Kyoto University Hospital, 54, Kawahara-cyo, Syogoin, Sakyo-ku, Kyoto City, Kyoto, 606-8507, Japan
| | - Takahiro Horimatsu
- Kyoto University Hospital, 54, Kawahara-cyo, Syogoin, Sakyo-ku, Kyoto City, Kyoto, 606-8507, Japan
| | - Tadao Tsuboyama
- Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, 53, Kawahara-cho, Syogoin, Sakyo-ku, Kyoto City, Kyoto, 606-8507, Japan
| | - Kanae Matsushima
- Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, 53, Kawahara-cho, Syogoin, Sakyo-ku, Kyoto City, Kyoto, 606-8507, Japan
| | - Toshihiro Kato
- Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, 53, Kawahara-cho, Syogoin, Sakyo-ku, Kyoto City, Kyoto, 606-8507, Japan
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38
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Yang Y, Luo L, Cai X, Fang Y, Wang J, Chen G, Yang J, Zhou Q, Sun X, Cheng X, Yan H, Lu W, Hu C, Cao P. Nrf2 inhibits oxaliplatin-induced peripheral neuropathy via protection of mitochondrial function. Free Radic Biol Med 2018. [PMID: 29530794 DOI: 10.1016/j.freeradbiomed.2018.03.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Oxaliplatin-induced peripheral neuropathy (OIPN) is a severe, dose-limiting toxicity associated with cancer chemotherapy. The efficacy of antioxidant administration in OIPN is debatable, as the promising preliminary results obtained with a number of antioxidants have not been confirmed in larger clinical trials. Besides its antioxidant activity, the transcription factor, nuclear factor-erythroid 2 (NF-E2) p45-related factor 2 (Nrf2) plays a crucial role in the maintenance of mitochondrial homeostasis, and mitochondrial dysfunction is a key contributor to OIPN. Here, we have investigated the protective properties of Nrf2 in OIPN. Nrf2-/- mice displayed severe mechanical allodynia and cold sensitivity and thus experienced increased peripheral nervous system injury compared to Nrf2+/+ mice. Furthermore, Nrf2 knockout aggravated oxaliplatin-induced reactive oxygen species production, decreased the mitochondrial membrane potential, led to abnormal intracellular calcium levels, and induced cytochrome c-related apoptosis and overexpression of the TRP protein family. Sulforaphane-induced activation of the Nrf2 signaling pathway alleviated morphological alterations, mitochondrial dysfunction in dorsal root ganglion neurons, and nociceptive sensations in mice. Our findings reveal that Nrf2 may play a critical role in ameliorating OIPN, through protection of mitochondrial function by alleviating oxidative stress and inhibiting TRP protein family expression. This suggests that pharmacological or therapeutic activation of Nrf2 may be used to prevent or slow down the progression of OIPN.
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Affiliation(s)
- Yang Yang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210097, China
| | - Lan Luo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210097, China
| | - Xueting Cai
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Yuan Fang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Jiaqi Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Gang Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Jie Yang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Qian Zhou
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Xiaoyan Sun
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Xiaolan Cheng
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Huaijiang Yan
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Wuguang Lu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Chunping Hu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China
| | - Peng Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, #100 Shizi Street, Hongshan Road, Nanjing 210028, Jiangsu, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China.
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De Ieso ML, Yool AJ. Mechanisms of Aquaporin-Facilitated Cancer Invasion and Metastasis. Front Chem 2018; 6:135. [PMID: 29922644 PMCID: PMC5996923 DOI: 10.3389/fchem.2018.00135] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 04/09/2018] [Indexed: 01/02/2023] Open
Abstract
Cancer is a leading cause of death worldwide, and its incidence is rising with numbers expected to increase 70% in the next two decades. The fact that current mainline treatments for cancer patients are accompanied by debilitating side effects prompts a growing demand for new therapies that not only inhibit growth and proliferation of cancer cells, but also control invasion and metastasis. One class of targets gaining international attention is the aquaporins, a family of membrane-spanning water channels with diverse physiological functions and extensive tissue-specific distributions in humans. Aquaporins−1,−2,−3,−4,−5,−8, and−9 have been linked to roles in cancer invasion, and metastasis, but their mechanisms of action remain to be fully defined. Aquaporins are implicated in the metastatic cascade in processes of angiogenesis, cellular dissociation, migration, and invasion. Cancer invasion and metastasis are proposed to be potentiated by aquaporins in boosting tumor angiogenesis, enhancing cell volume regulation, regulating cell-cell and cell-matrix adhesions, interacting with actin cytoskeleton, regulating proteases and extracellular-matrix degrading molecules, contributing to the regulation of epithelial-mesenchymal transitions, and interacting with signaling pathways enabling motility and invasion. Pharmacological modulators of aquaporin channels are being identified and tested for therapeutic potential, including compounds derived from loop diuretics, metal-containing organic compounds, plant natural products, and other small molecules. Further studies on aquaporin-dependent functions in cancer metastasis are needed to define the differential contributions of different classes of aquaporin channels to regulation of fluid balance, cell volume, small solute transport, signal transduction, their possible relevance as rate limiting steps, and potential values as therapeutic targets for invasion and metastasis.
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Affiliation(s)
- Michael L De Ieso
- Department of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Andrea J Yool
- Department of Physiology, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
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Wesselink E, Winkels RM, van Baar H, Geijsen AJMR, van Zutphen M, van Halteren HK, Hansson BME, Radema SA, de Wilt JHW, Kampman E, Kok DEG. Dietary Intake of Magnesium or Calcium and Chemotherapy-Induced Peripheral Neuropathy in Colorectal Cancer Patients. Nutrients 2018; 10:E398. [PMID: 29570617 PMCID: PMC5946183 DOI: 10.3390/nu10040398] [Citation(s) in RCA: 16] [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: 02/15/2018] [Revised: 03/15/2018] [Accepted: 03/21/2018] [Indexed: 01/22/2023] Open
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe side-effect in colorectal cancer (CRC) patients. This study assessed the association between habitual dietary intake of magnesium or calcium and prevalence and severity of chronic CIPN in CRC patients receiving adjuvant chemotherapy. For this prospective cohort study, 196 CRC patients were considered. Magnesium and calcium intake was determined using a food frequency questionnaire at diagnosis, during and after chemotherapy. Chronic CIPN was assessed 12 months after diagnosis using the quality of life questionnaire CIPN20. Prevalence ratios were calculated to assess the association between magnesium or calcium intake and the prevalence of CIPN. Multivariable linear regression analysis was used to assess the association between magnesium or calcium intake and severity of CIPN. CIPN was reported by 160 (82%) patients. Magnesium intake during chemotherapy was statistically significantly associated with lower prevalence of CIPN (prevalence ratio (PR) 0.53, 95% confidence interval (CI) 0.32, 0.92). Furthermore, higher dietary intake of magnesium during (β -1.08, 95% CI -1.95, -0.22) and after chemotherapy (β -0.93, 95% CI -1.81, -0.06) was associated with less severe CIPN. No associations were found for calcium intake and the prevalence and severity of CIPN. To conclude, we observed an association between higher dietary magnesium intake and lower prevalence and severity of CIPN in CRC patients.
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Affiliation(s)
- Evertine Wesselink
- Division of Human Nutrition, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
| | - Renate M Winkels
- Division of Human Nutrition, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
| | - Harm van Baar
- Division of Human Nutrition, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
| | - Anne J M R Geijsen
- Division of Human Nutrition, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
| | - Moniek van Zutphen
- Division of Human Nutrition, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
| | - Henk K van Halteren
- Department of Internal Medicine, Admiraal de Ruyter Ziekenhuis, 's-Gravenpolderseweg 114, 4462 RA Goes, The Netherlands.
| | - Bibi M E Hansson
- Department of Surgery, Canisius Wilhelmina Ziekenhuis, Weg door het Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands.
| | - Sandra A Radema
- Department of Medical Oncology, Radboud University Medical Centre, Geert Grooteplein-Zuid 22, 6525 GA Nijmegen, The Netherlands.
| | - Johannes H W de Wilt
- Department of Surgery, Radboud University Medical Centre, Geert Grooteplein-Zuid 22, 6525 GA Nijmegen, The Netherlands.
| | - Ellen Kampman
- Division of Human Nutrition, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
| | - Dieuwertje E G Kok
- Division of Human Nutrition, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
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Forstenpointner J, Oberlojer VC, Naleschinski D, Höper J, Helfert SM, Binder A, Gierthmühlen J, Baron R. A-Fibers Mediate Cold Hyperalgesia in Patients with Oxaliplatin-Induced Neuropathy. Pain Pract 2018; 18:758-767. [DOI: 10.1111/papr.12670] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 11/23/2017] [Indexed: 11/30/2022]
Affiliation(s)
- Julia Forstenpointner
- Division of Neurological Pain Research and Therapy; Department of Neurology; University Hospital Schleswig-Holstein; Kiel Germany
| | - Violetta C. Oberlojer
- Division of Neurological Pain Research and Therapy; Department of Neurology; University Hospital Schleswig-Holstein; Kiel Germany
| | - Dennis Naleschinski
- Division of Neurological Pain Research and Therapy; Department of Neurology; University Hospital Schleswig-Holstein; Kiel Germany
| | - Johanna Höper
- Division of Neurological Pain Research and Therapy; Department of Neurology; University Hospital Schleswig-Holstein; Kiel Germany
| | - Stephanie M. Helfert
- Division of Neurological Pain Research and Therapy; Department of Neurology; University Hospital Schleswig-Holstein; Kiel Germany
| | - Andreas Binder
- Division of Neurological Pain Research and Therapy; Department of Neurology; University Hospital Schleswig-Holstein; Kiel Germany
| | - Janne Gierthmühlen
- Division of Neurological Pain Research and Therapy; Department of Neurology; University Hospital Schleswig-Holstein; Kiel Germany
| | - Ralf Baron
- Division of Neurological Pain Research and Therapy; Department of Neurology; University Hospital Schleswig-Holstein; Kiel Germany
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42
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Heide R, Bostock H, Ventzel L, Grafe P, Bergmans J, Fuglsang-Frederiksen A, Finnerup NB, Tankisi H. Axonal excitability changes and acute symptoms of oxaliplatin treatment: In vivo evidence for slowed sodium channel inactivation. Clin Neurophysiol 2017; 129:694-706. [PMID: 29233604 DOI: 10.1016/j.clinph.2017.11.015] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 10/16/2017] [Accepted: 11/05/2017] [Indexed: 01/28/2023]
Abstract
OBJECTIVE Neurotoxicity is the most frequent dose-limiting side effect of the anti-cancer agent oxaliplatin, but the mechanisms are not well understood. This study used nerve excitability testing to investigate the pathophysiology of the acute neurotoxicity. METHODS Questionnaires, quantitative sensory tests, nerve conduction studies and nerve excitability testing were undertaken in 12 patients with high-risk colorectal cancer treated with adjuvant oxaliplatin and in 16 sex- and age-matched healthy controls. Examinations were performed twice for patients: once within 3 days after oxaliplatin treatment (post-infusion examination) and once shortly before the following treatment (recovery examination). RESULTS The most frequent post-infusion symptoms were tingling paresthesias and cold allodynia. The most prominent nerve excitability change was decreased superexcitability of motor axons which correlated with the average intensity of abnormal sensations (Spearman Rho = 0.80, p < .01). The motor nerve excitability changes were well modeled by a slowing of sodium channel inactivation, and were proportional to dose/m2 with a half-life of about 10d. CONCLUSIONS Oxaliplatin induces reversible slowing of sodium channel inactivation in motor axons, and these changes are closely related to the reversible cold allodynia. However, further studies are required due to small sample size in this study. SIGNIFICANCE Nerve excitability data provide an index of sodium channel dysfunction: an objective biomarker of acute oxaliplatin neurotoxicity.
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Affiliation(s)
- Rikke Heide
- Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark; Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Hugh Bostock
- Institute of Neurology, Queen Square House, London, United Kingdom
| | - Lise Ventzel
- Department of Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Grafe
- Institute of Physiology, Ludwig-Maximilians University Munich, Munich, Germany
| | - Joseph Bergmans
- Laboratory of Clinical Neurophysiology, Faculty of Medicine, University of Louvain, Brussels, Belgium
| | | | - Nanna B Finnerup
- Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Hatice Tankisi
- Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark.
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43
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Ji WB, Hong KD, Kim JS, Joung SY, Um JW, Min BW. Effect of a Shortened Duration of FOLFOX Chemotherapy on the Survival Rate of Patients with Stage II and III Colon Cancer. Chemotherapy 2017; 63:8-12. [PMID: 29130943 DOI: 10.1159/000481566] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 09/16/2017] [Indexed: 12/26/2022]
Abstract
BACKGROUND FOLFOX chemotherapy is widely used as an adjuvant treatment for advanced colon cancer. The duration of adjuvant chemotherapy is usually set to 6 months, which is based on a former study of 5-fluorouracil/leucovorin chemotherapy. However, the FOLFOX regimen is known to have complications, such as peripheral neuropathy. The aim of this study was to compare the survival rates and complications experienced by patients receiving either 4 or 6 months of FOLFOX chemotherapy. METHODS Retrospective data analysis was performed for stage II and III patients who underwent radical resection of colon cancer. We compared the 5-year survival rates and the occurrence of complications in patients who completed only 8 cycles of FOLFOX chemotherapy with patients who completed 12 cycles of chemotherapy. RESULTS Among 188 patients who underwent adjuvant FOLFOX chemotherapy for stage II or III colon cancer, 83 (44.1%) completed 6 months of FOLFOX chemotherapy and 64 (34.0%) patients discontinued after 4 months of chemotherapy. The 5-year overall survival and disease-free survival rates did not show a significant difference. Patients in the 6-month group had peripheral neuropathy more frequently (p = 0.028). CONCLUSIONS Five-year overall and disease-free survival were not significantly different between the 2 groups. Large-scale prospective studies are necessary for the analysis of complications and survival rates.
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Affiliation(s)
- Woong Bae Ji
- Department of Colorectal Surgery, Korea University Ansan Hospital, Ansan, Republic of Korea
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Griffith KA, Zhu S, Johantgen M, Kessler MD, Renn C, Beutler AS, Kanwar R, Ambulos N, Cavaletti G, Bruna J, Briani C, Argyriou AA, Kalofonos HP, Yerges-Armstrong LM, Dorsey SG. Oxaliplatin-Induced Peripheral Neuropathy and Identification of Unique Severity Groups in Colorectal Cancer. J Pain Symptom Manage 2017; 54:701-706.e1. [PMID: 28743660 PMCID: PMC5659746 DOI: 10.1016/j.jpainsymman.2017.07.033] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 07/17/2017] [Accepted: 07/18/2017] [Indexed: 01/27/2023]
Abstract
CONTEXT Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity of oxaliplatin and affects most colorectal cancer patients. OIPN is commonly evaluated by patient symptom report, using scales to reflect impairment. They do not discriminate between unique grouping of symptoms and signs, which impedes prompt identification of OIPN. OBJECTIVE The objective of this study was to identify clusters of symptoms and signs that differentiated underlying clinical severity and segregated patients within our population into OIPN subgroups. METHODS Chemotherapy-naive colorectal cancer patients (N = 148) receiving oxaliplatin were administered the Total Neuropathy Score clinical (TNSc©), which includes symptom report (sensory, motor, autonomic) and sensory examination (pin sense, vibration, reflexes). The TNSc was administered before chemotherapy initiation (T0) and after cumulative doses of oxaliplatin 510-520 mg/m2 (T1) and 1020-1040 mg/m2 of oxaliplatin (T2). Using mean T2 TNSc scores, latent class analysis grouped patients into OIPN severity cohorts. RESULTS Latent class analysis categorized patients into four distinct OIPN groups: low symptoms and low signs (n = 54); low symptoms and intermediate signs (n = 44); low symptoms and high signs (n = 21); and high symptoms and high signs (n = 29). No differences were noted among OIPN groups on age, sex, chemotherapy regimen, or cumulative oxaliplatin dose. CONCLUSION We identified OIPN patient groups with distinct symptoms/signs, demonstrating variability of OIPN presentation regardless of cumulative oxaliplatin dose. Over half of the sample had positive findings on OIPN examination despite little or no symptoms. Sensory examination of all patients receiving oxaliplatin is indicated for timely identification of OIPN, which will allow earlier symptom management.
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Affiliation(s)
- Kathleen A Griffith
- Department of Pain and Translational Symptom Science, School of Nursing, University of Maryland, Baltimore, Maryland, USA; Program in Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
| | - Shijun Zhu
- Department of Organizational Systems and Adult Health, School of Nursing, University of Maryland, Baltimore, Maryland, USA
| | - Meg Johantgen
- Department of Organizational Systems and Adult Health, School of Nursing, University of Maryland, Baltimore, Maryland, USA
| | - Michael D Kessler
- Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Cynthia Renn
- Department of Pain and Translational Symptom Science, School of Nursing, University of Maryland, Baltimore, Maryland, USA; Program in Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA; UM Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland, USA
| | - Andreas S Beutler
- Department of Oncology and the Cancer Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Rahul Kanwar
- Department of Oncology and the Cancer Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Nicholas Ambulos
- Program in Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Guido Cavaletti
- School of Medicine and Surgery, Experimental Neurology Unit and Milan Center for Neuroscience, University of Milano-Bicocca, Monza (MB), Italy
| | - Jordi Bruna
- Unit of Neuro-Oncology, Bellvitge University Hospital-ICO Duran and Reynals, L'hospitale Barcelona, Spain
| | - Chiara Briani
- Department of Neurosciences, University of Padua, Padua, Italy
| | - Andreas A Argyriou
- Division of Oncology, Department of Medicine, University Hospital of Patras, Rion-Patras, Greece
| | - Haralabos P Kalofonos
- Division of Oncology, Department of Medicine, University Hospital of Patras, Rion-Patras, Greece
| | - Laura M Yerges-Armstrong
- Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Susan G Dorsey
- Department of Pain and Translational Symptom Science, School of Nursing, University of Maryland, Baltimore, Maryland, USA; Program in Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA; UM Center to Advance Chronic Pain Research, University of Maryland, Baltimore, Maryland, USA
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45
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Jefford M, Emery J, Grunfeld E, Martin A, Rodger P, Murray AM, De Abreu Lourenco R, Heriot A, Phipps-Nelson J, Guccione L, King D, Lisy K, Tebbutt N, Burgess A, Faragher I, Woods R, Schofield P. SCORE: Shared care of Colorectal cancer survivors: protocol for a randomised controlled trial. Trials 2017; 18:506. [PMID: 29084595 PMCID: PMC5663101 DOI: 10.1186/s13063-017-2245-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 10/10/2017] [Indexed: 12/20/2022] Open
Abstract
Background Colorectal cancer (CRC) is the most common cancer affecting both men and women. Survivors of CRC often experience various physical and psychological effects arising from CRC and its treatment. These effects may last for many years and adversely affect QoL, and they may not be adequately addressed by standard specialist-based follow-up. Optimal management of these effects should harness the expertise of both primary care and specialist care. Shared models of care (involving both the patient’s primary care physician [PCP] and specialist) have the potential to better support survivors and enhance health system efficiency. Methods/design SCORE (Shared care of Colorectal cancer survivors) is a multisite randomised controlled trial designed to optimise and operationalise a shared care model for survivors of CRC, to evaluate the acceptability of the intervention and study processes, and to collect preliminary data regarding the effects of shared care compared with usual care on a range of patient-reported outcomes. The primary outcome is QoL measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Secondary outcomes are satisfaction with care, unmet needs, continuity of care and health resource use. The shared care model involves replacement of two routine specialist follow-up visits with PCP visits, as well as the provision of a tailored survivorship care plan and a survivorship booklet and DVD for CRC survivors. All consenting patients will be randomised 1:1 to either shared care or usual care and will complete questionnaires at three time points over a 12-month period (baseline and at 6 and 12 months). Health care resource use data will also be collected and used to evaluate costs. Discussion The evaluation and implementation of models of care that are responsive to the holistic needs of cancer survivors while reducing the burden on acute care settings is an international priority. Shared care between specialists and PCPs has the potential to enhance patient care and outcomes for CRC survivors while offering improvements in health care resource efficiency. If the findings of the present study show that the shared care intervention is acceptable and feasible for CRC survivors, the intervention may be readily expanded to other groups of cancer survivors. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12617000004369p. Registered on 3 January 2017; protocol version 4 approved 24 February 2017. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2245-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Michael Jefford
- Department of Cancer Experiences Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. .,Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia. .,Division of Cancer Medicine, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.
| | - Jon Emery
- Department of General Practice and Centre for Cancer Research, University of Melbourne, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia
| | - Eva Grunfeld
- Ontario Institute for Cancer Research, Toronto, ON, Canada.,Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
| | - Andrew Martin
- National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
| | - Paula Rodger
- Department of Cancer Experiences Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Alexandra M Murray
- Department of Cancer Experiences Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Richard De Abreu Lourenco
- Centre for Health Economics Research and Evaluation, University of Technology Sydney, Sydney, NSW, Australia
| | - Alexander Heriot
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Jo Phipps-Nelson
- Department of Cancer Experiences Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Lisa Guccione
- Department of Cancer Experiences Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Psychology Department, School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Dorothy King
- Department of Cancer Experiences Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Karolina Lisy
- Department of Cancer Experiences Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Niall Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - Adele Burgess
- Colorectal Surgery Unit, Austin Health, Heidelberg, VIC, Australia
| | - Ian Faragher
- Colorectal Surgery, Western Health, Footscray, VIC, Australia
| | - Rodney Woods
- Colorectal Surgery Unit, St Vincent's Hospital, Fitzroy, VIC, Australia
| | - Penelope Schofield
- Department of Cancer Experiences Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia.,Department of Psychology, School of Health Sciences, Faculty of Health, Arts and Design, Swinburne University of Technology, Heidelberg, VIC, Australia
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46
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Garrett MJ, Waddell JA, Solimando DA. Capecitabine, Oxaliplatin, and Bevacizumab (BCapOx) Regimen for Metastatic Colorectal Cancer. Hosp Pharm 2017; 52:341-347. [PMID: 28804149 DOI: 10.1177/0018578717715353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc, 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. The information presented in this review is based on published data and clinical expertise and includes information not included in the product labeling. Incorporation of such published data provides a more robust assessment of the drugs and assists pharmacists in evaluation of orders for off-label use of these agents.
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Affiliation(s)
| | - J Aubrey Waddell
- Blount Memorial Hospital, Maryville, TN, USA.,Blount Memorial Hospital, Maryville, TN, USA
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47
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Hucke A, Ciarimboli G. The Role of Transporters in the Toxicity of Chemotherapeutic Drugs: Focus on Transporters for Organic Cations. J Clin Pharmacol 2017; 56 Suppl 7:S157-72. [PMID: 27385173 DOI: 10.1002/jcph.706] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Revised: 12/11/2015] [Accepted: 01/06/2016] [Indexed: 12/11/2022]
Abstract
The introduction of chemotherapy in the treatment of cancer is one of the most important achievements of modern medicine, even allowing the cure of some lethal diseases such as testicular cancer and other malignant neoplasms. The number and type of chemotherapeutic agents available have steadily increased and have developed until the introduction of targeted tumor therapy. It is now evident that transporters play an important role for determining toxicity of chemotherapeutic drugs not only against target but also against nontarget cells. This is of special importance for intracellularly active hydrophilic drugs, which cannot freely penetrate the plasma membrane. Because many important chemotherapeutic agents are substrates of transporters for organic cations, this review discusses the known interaction of these substances with these transporters. A particular focus is given to the role of transporters for organic cations in the development of side effects of chemotherapy with platinum derivatives and in the efficacy of recently developed tyrosine kinase inhibitors to specifically target cancer cells. It is evident that specific inhibition of uptake transporters may be a possible strategy to protect against undesired side effects of platinum derivatives without compromising their antitumor efficacy. These transporters are also important for efficient targeting of tyrosine kinase inhibitors to cancer cells. However, in order to achieve the aims of protecting from undesired toxicities and improving the specificity of uptake by tumor cells, an exact knowledge of transporter expression, function, regulation under normal and pathologic conditions, and of genetically and epigenetically regulation is mandatory.
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Affiliation(s)
- Anna Hucke
- Experimental Nephrology, Medical Clinic D, Münster University Hospital, Münster, Germany
| | - Giuliano Ciarimboli
- Experimental Nephrology, Medical Clinic D, Münster University Hospital, Münster, Germany
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48
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Waddell JA, Solimando DA. Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX 6 and 7) Regimens for Colorectal Cancer. Hosp Pharm 2017. [DOI: 10.1177/001857870504000805] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The increasing complexity of cancer chemotherapy heightens the requirement that pharmacists be familiar with these highly toxic agents. This column will review various issues related to preparation, dispensing, and administration of cancer chemotherapy. It will also serve as a review of various agents, both commercially available and investigational, used to treat malignant diseases.
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Affiliation(s)
- J. Aubrey Waddell
- Oncology Pharmacy Residency Program, Department of Pharmacy, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Rm 2P02, Washington, DC 20307
| | - Dominic A. Solimando
- Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203
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49
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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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50
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Fu X, Wu H, Li J, Wang C, Li M, Ma Q, Yang W. Efficacy of Drug Interventions for Chemotherapy-Induced Chronic Peripheral Neurotoxicity: A Network Meta-analysis. Front Neurol 2017. [PMID: 28642731 PMCID: PMC5462987 DOI: 10.3389/fneur.2017.00223] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Peripheral neurotoxicity is a disturbing issue for cancer patients who are treated with chemotherapy. Several medications have been developed for preventing chemotherapy-induced chronic neurotoxicity (CICNT) however; their relative efficacies have not yet been studied. In this study, we conducted a network meta-analysis to give intervention recommendations. The literature was searched in a variety of databases and eligible studies were chosen based on predefined criteria. Data extraction and statistical analysis was performed, and the results are displayed using the odds ratio (OR) and corresponding 95% credible intervals (CrI) with respect to overall and severe neurotoxicity. The medications were ranked according to their surface under cumulative ranking curve values. The consistency of direct and indirect evidence was also evaluated. We found that patients with amifostine or vitamin E (VE) treatment exhibited a lower risk of overall neurotoxicity compared to those using the placebo (amifostine: OR = 0.10, 95% CrI: 0.02–0.46; VE: OR = 0.08, 95% CrI: 0.01–0.99). In regard to preventing severe neurotoxicity, glutathione and amifostine treatment appeared to be significantly more effective than the placebo (glutathione: OR = 0.19, 95% CrI: 0.04–0.64; amifostine: OR = 0.12, 95% CrI: 0.02–0.48). In summary, amifostine, VE, and glutathione treatment is considered to be effective in lowering the risk of CICNT. However, further studies which consider safety are required.
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Affiliation(s)
- Xiying Fu
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Huijie Wu
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jinyao Li
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Can Wang
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Ming Li
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Qianqian Ma
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Yang
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
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