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Barary M, Hosseinzadeh R, Kazemi S, Liang JJ, Mansoori R, Sio TT, Hosseini M, Moghadamnia AA. The effect of propolis on 5-fluorouracil-induced cardiac toxicity in rats. Sci Rep 2022; 12:8661. [PMID: 35606482 PMCID: PMC9127097 DOI: 10.1038/s41598-022-12735-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 05/16/2022] [Indexed: 12/14/2022] Open
Abstract
5-Fluorouracil (5-FU) is one of the most common chemotherapeutic agents used in treating solid tumors, and the 5-FU-induced cardiotoxicity is the second cause of cardiotoxicity induced by chemotherapeutic drugs. Propolis (Pro) has vigorous anti-inflammatory activity. Its cardio-protective characteristic against doxorubicin-induced cardiotoxicity was previously proven. The current study aimed to appraise the effect of Pro on 5-FU-induced cardiotoxicity in rats. Twenty-four male Wistar rats were divided into four groups: Control, 5-FU, 5-FU + Pro 250 mg/kg, and 5-FU + Colchicine (CLC) 5 mg/kg. Different hematological, serological, biochemical, histopathological, and molecular assays were performed to assess the study's aim. Moreover, a rat myocardium (H9C2(2-1)) cell line was also used to assess this protective effect in-vitro. 5-FU resulted in significant cardiotoxicity represented by an increase in malondialdehyde (MDA) levels, cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) expression, cardiac enzyme levels, and histopathological degenerations. 5-FU treatment also decreased bodyweight, total anti-oxidant capacity (TAC), catalase (CAT) levels, blood cell counts, and hemoglobin (Hb) levels. In addition, 5-FU disrupted ECG parameters, including increased elevation in the ST-segment and increased QRS complex and QTc duration. Treating with Pro reduced oxidative stress, cardiac enzymes, histopathological degenerations, and COX-2 expression in cardiac tissue alleviated ECG disturbances and increased the number of blood cells and TAC levels. Moreover, 5-FU-induced bodyweight loss was ameliorated after treatment with Pro. Our results demonstrated that treatment with Pro significantly improved cardiotoxicity induced by 5-FU in rats.
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Affiliation(s)
- Mohammad Barary
- Student Research Committee, Virtual School of Medical Education and Management, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Rezvan Hosseinzadeh
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Jackson J Liang
- Division of Cardiovascular Medicine, Cardiac Arrhythmia Service, University of Michigan, Ann Arbor, MI, USA
| | - Razieh Mansoori
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Terence T Sio
- Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA
| | - Mohammad Hosseini
- Department of Veterinary Parasitology, Babol-Branch, Islamic Azad University, Babol, Iran
| | - Ali Akbar Moghadamnia
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran.
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More LA, Lane S, Asnani A. 5-FU Cardiotoxicity: Vasospasm, Myocarditis, and Sudden Death. Curr Cardiol Rep 2021; 23:17. [PMID: 33537861 DOI: 10.1007/s11886-021-01441-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/08/2021] [Indexed: 01/08/2023]
Abstract
PURPOSE OF REVIEW 5-fluorouracil (5-FU) is one of the most common causes of cardiotoxicity associated with chemotherapy. The manifestations of 5-FU cardiotoxicity are diverse, and there are no established clinical guidelines addressing the diagnosis and management of this condition. Here we summarize the mechanistic and clinical data available to guide clinicians in caring for patients with suspected 5-FU cardiotoxicity. RECENT FINDINGS The decision to resume 5-FU treatment in patients with suspected cardiovascular toxicity remains challenging. Testing for predisposing genetic variants may be helpful, particularly in patients with other signs of 5-FU toxicity. Uridine triacetate is a recently approved antidote that can improve clinical outcomes in patients with life-threatening fluoropyrimidine cardiotoxicity. 5-FU cardiotoxicity remains poorly understood, with limited mechanistic or prospective clinical trial data available to define risk factors or effective management strategies. Risk stratification and therapeutic decisions should be individualized, based on the risk-benefit ratio of continuing 5-FU therapy for each patient.
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Affiliation(s)
- Luis Alberto More
- CardioVascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Sarah Lane
- CardioVascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Aarti Asnani
- CardioVascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. .,Harvard Medical School, Boston, MA, USA. .,Center for Life Sciences, 3 Blackfan Circle, Room 911, Boston, MA, 02215, USA.
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Kanda T, Wakai A, Chida T, Nakamura Y. S1-induced vasospastic angina-diagnostic utility of Holter ECG: a report of a case. Surg Case Rep 2020; 6:217. [PMID: 32833093 PMCID: PMC7445223 DOI: 10.1186/s40792-020-00975-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 08/04/2020] [Indexed: 12/03/2022] Open
Abstract
Background Vasospastic angina is a rare but potentially life-threatening adverse event (AE) of S1, an oral fluoropyrimidine anticancer agent. However, this AE is not well known owing to its low incidence. We report herein a case of a patient who suffered from vasospastic angina associated with S1 chemotherapy for unresectable gastric adenocarcinoma, along with a review of the literature. Case presentation A 68-year-old woman was endoscopically diagnosed with gastric adenocarcinoma of the diffuse type. Abdominal pelvic contrast-enhanced computed tomography (CT) revealed small nodules in the omentum and ascites in the pouch of Douglas. The patient was clinically diagnosed with unresectable gastric adenocarcinoma with peritoneal metastasis, and primary chemotherapy with S1 plus cisplatin was selected. Around midnight of day 1, the patient complained of sudden oppressive chest pain. The pain disappeared spontaneously after 3–5 min, but similar events happened every midnight thereafter. No significant change was found on bedside electrocardiograms (ECGs) recorded immediately after the pain attacks. The patient was suspected to have unstable angina and underwent Holter ECG on day 4 of treatment. Holter ECG revealed ST segment elevations and short-run ventricular tachycardia during a pain attack. S1 chemotherapy was discontinued, and no attack was observed thereafter. Coronary CT angiography showed no significant stenosis of coronary arteries. Conclusions Clinicians should be aware of vasospastic angina as a serious AE in the chemotherapy with S1. Holter ECG is useful for the early diagnosis of this rare and clinically important AE.
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Affiliation(s)
- Tatsuo Kanda
- Department of Surgery, Sanjo General Hospital, Tsukanome, Sanjo, Niigata, 955-0055, Japan.
| | - Atsuhiro Wakai
- Department of Surgery, Sanjo General Hospital, Tsukanome, Sanjo, Niigata, 955-0055, Japan
| | - Tadasu Chida
- Department of Surgery, Sanjo General Hospital, Tsukanome, Sanjo, Niigata, 955-0055, Japan
| | - Yuichi Nakamura
- Department of Cardiology, Nagaoka Chuo General Hospital, Nagaoka, Japan
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4
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Mishra T, Shokr M, Ahmed A, Afonso L. Acute reversible left ventricular systolic dysfunction associated with 5-fluorouracil therapy: a rare and increasingly recognised cardiotoxicity of a commonly used drug. BMJ Case Rep 2019; 12:12/9/e230499. [PMID: 31519717 DOI: 10.1136/bcr-2019-230499] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
5-Fluorouracil (5-FU) is the third most common chemotherapeutic agent for treating solid cancers and the second most common to cause cardiotoxicity. We present a rare case of acute reversible severe left ventricular systolic dysfunction associated with 5-FU. A 54-year-old woman with a history of stage IV gastric cancer presented with features of transient ischaemic attack after receiving the first dose of FLOT (5-FU, leucovorin, oxaliplatin and docetaxel). During the diagnostic workup, it was found that her ejection fraction was severely reduced to 15% with features of global hypokinesis, which later improved back to 65% within 13 days. These cases challenge our current understanding of the underlying mechanisms of this cardiotoxicity. Additionally, even though the patient did not experience any cardiac symptoms, it is important to monitor these patients closely as they are at high risk for fatal complications like arrhythmia and thrombus formation.
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Affiliation(s)
- Tushar Mishra
- Department of Internal Medicine, Wayne State University, Detroit, Michigan, USA
| | - Mohamed Shokr
- Division of Cardiology, Wayne State University, Detroit, Michigan, USA
| | - Abdelrahman Ahmed
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Luis Afonso
- Division of Cardiology, Wayne State University, Detroit, Michigan, USA
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Abstract
Fluoropyrimidines are chemotherapeutic agents that confer great benefit to many patients with solid tumors, but their use is often limited by cardiotoxicity. The incidence and precise mechanisms of cardiotoxicity remain uncertain. Clinical presentations of fluoropyrimidine toxicity are varied and include chest pain, myocardial infarction, acute cardiomyopathy, arrhythmia, cardiogenic shock, and sudden cardiac death. Proposed mechanisms include coronary vasospasm, coronary endothelial dysfunction, direct myocardial toxicity, myocarditis, and Takotsubo cardiomyopathy. Therapeutic and prophylactic interventions primarily target coronary vasospasm as the underlying cause. Prospective studies are needed to develop evidence-based approaches to cardioprotection in patients receiving fluoropyrimidines.
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Affiliation(s)
- Jaya Kanduri
- Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Luis Alberto More
- CardioVascular Institute, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Center for Life Sciences 9th Floor, Boston, MA 02215, USA
| | - Anuradha Godishala
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Aarti Asnani
- Cardio-Oncology Program, Division of Cardiovascular Medicine, CardioVascular Institute, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, Center for Life Sciences Room 911, Boston, MA 02215, USA.
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The Main Metabolites of Fluorouracil + Adriamycin + Cyclophosphamide (FAC) Are Not Major Contributors to FAC Toxicity in H9c2 Cardiac Differentiated Cells. Biomolecules 2019; 9:biom9030098. [PMID: 30862114 PMCID: PMC6468772 DOI: 10.3390/biom9030098] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/21/2019] [Accepted: 03/01/2019] [Indexed: 02/07/2023] Open
Abstract
In the clinical practice, the combination of 5-fluorouracil (5-FU) + Adriamycin (also known as doxorubicin, DOX) + cyclophosphamide (CYA) (known as FAC) is used to treat breast cancer. The FAC therapy, however, carries some serious risks, namely potential cardiotoxic effects, although the mechanisms are still unclear. In the present study, the role of the main metabolites regarding FAC-induced cardiotoxicity was assessed at clinical relevant concentrations. Seven-day differentiated H9c2 cells were exposed for 48 h to the main metabolites of FAC, namely the metabolite of 5-FU, α-fluoro-β-alanine (FBAL, 50 or 100 μM), of DOX, doxorubicinol (DOXOL, 0.2 or 1 μM), and of CYA, acrolein (ACRO, 1 or 10 μM), as well as to their combination. The parent drugs (5-FU 50 μM, DOX 1 μM, and CYA 50 μM) were also tested isolated or in combination with the metabolites. Putative cytotoxicity was evaluated through phase contrast microscopy, Hoechst staining, membrane mitochondrial potential, and by two cytotoxicity assays: the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and the neutral red (NR) lysosomal incorporation. The metabolite DOXOL was more toxic than FBAL and ACRO in the MTT and NR assays. When in combination, neither FBAL nor ACRO increased DOXOL-induced cytotoxicity. No nuclear condensation was observed for any of the tested combinations; however, a significant mitochondrial potential depolarization after FBAL 100 μM + DOXOL 1 μM + ACRO 10 μM or FBAL 100 μM + DOXOL 1 μM exposure was seen at 48 h. When tested alone DOX 1 μM was more cytotoxic than all the parent drugs and metabolites in both the cytotoxicity assays performed. These results demonstrated that DOXOL was the most toxic of all the metabolites tested; nonetheless, the metabolites do not seem to be the major contributors to FAC-induced cardiotoxicity in this cardiac model.
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Sara JD, Kaur J, Khodadadi R, Rehman M, Lobo R, Chakrabarti S, Herrmann J, Lerman A, Grothey A. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol 2018; 10:1758835918780140. [PMID: 29977352 PMCID: PMC6024329 DOI: 10.1177/1758835918780140] [Citation(s) in RCA: 259] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/25/2018] [Indexed: 12/15/2022] Open
Abstract
Fluoropyrimidines such as 5-fluorouracil (5-FU) form the foundation of a wide variety of chemotherapy regimens. 5-FU is in fact the third most commonly used chemotherapeutic agent in the treatment of solid malignancies across the world. As with all chemotherapy, balancing the potential benefits of therapy against the risks of drug-related toxicity is crucial when clinicians and patients make shared decisions about treatment. 5-FU is the second most common chemotherapeutic drug associated with cardiotoxicity after anthracyclines, which can manifest as chest pain, acute coronary syndrome/myocardial infarction or death. Nevertheless a widespread appreciation of 5-FU-related cardiotoxicity and its implications is lacking amongst clinicians. In this review, we outline the incidence, possible risk factors, and likely pathophysiological mechanisms that may account for 5-FU-related cardiotoxicity and also highlight potential management strategies for this poorly understood clinical entity.
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Affiliation(s)
- Jaskanwal D Sara
- Department of Cardiovascular Diseases, Mayo College of Medicine, 200 First Street SW, Rochester, MN 55905-0001, USA
| | - Jasvinder Kaur
- Kent Oncology Centre, Maidstone and Tunbridge Wells NHS Trust, Maidstone, Kent, UK
| | - Ryan Khodadadi
- Department of Internal Medicine, Mayo College of Medicine, Rochester, MN, USA
| | - Muneeb Rehman
- Department of Internal Medicine, Mayo College of Medicine, Rochester, MN, USA
| | - Ronstan Lobo
- Department of Internal Medicine, Mayo College of Medicine, Rochester, MN, USA
| | - Sakti Chakrabarti
- Department of Medical Oncology, Mayo College of Medicine, Rochester, MN, USA
| | - Joerg Herrmann
- Department of Cardiovascular Diseases, Mayo College of Medicine, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo College of Medicine, Rochester, MN, USA
| | - Axel Grothey
- Department of Medical Oncology, Mayo College of Medicine, Rochester, MN, USA
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8
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Akhtar SS, Wani BA, Bano ZA, Salim KP, Handoo FA. 5-Fluorouracil-Induced Severe but Reversible Cardiogenic Shock: A Case Report. TUMORI JOURNAL 2018; 82:505-7. [PMID: 9063536 DOI: 10.1177/030089169608200522] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
5-fluorouracil cardiotoxicity is increasingly recognized with variable presentation. We report a patient who developed cardiogenic shock due to high-dose 5-fluorouracil infusion (1,000 mg/m2 every 24 hr for 96 hr). There was no evidence of myocardial necrosis. The patient recovered completely without any residual cardiac dysfunction. The exact cause of 5-fluorouracil toxicity remains to be determined. The case highlights the need for careful monitoring of patients who receive high-dose 5-fluorouracil for the development of cardiotoxicity.
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Affiliation(s)
- S S Akhtar
- Department of Medical Oncology, S.K. Institute of Medical Sciences, Soura Srinagar, Kashmir, India
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Precision cardio-oncology: understanding the cardiotoxicity of cancer therapy. NPJ Precis Oncol 2017; 1:31. [PMID: 29872712 PMCID: PMC5871905 DOI: 10.1038/s41698-017-0034-x] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 07/29/2017] [Accepted: 08/01/2017] [Indexed: 12/21/2022] Open
Abstract
Current oncologic treatments have brought a strong reduction in mortality in cancer patients. However, the cancer therapy-related cardiovascular complications, in particular chemo-therapy and radiation therapy-induced cardiotoxicities are a major cause of morbidity and mortality in people living with or surviving cancer. The simple fact is that all antineoplastic agents and radiation therapy target tumor cells but also result in collateral damage to other tissues including the cardiovascular system. The commonly used anthracycline chemotherapy agents can induce cardiomyopathy and congestive heart failure. Targeted therapies with human epidermal growth factor antibodies, tyrosine kinase inhibitors or vascular endothelial growth factor antibodies, and the antimetabolites also have shown to induce cardiomyopathy and myocardial ischemia. Cardiac arrhythmias and hypertension have been well described with the use of tyrosine kinase inhibitors and antimicrotubule agents. Pericarditis can happen with the use of cyclophosphamide or cytarabine. Mediastinal radiation can cause constrictive pericarditis, myocardial fibrosis, valvular lesions, and coronary artery disease. Despite significant progresses in the understanding of the molecular and pathophysiologic mechanisms behind the cardiovascular toxicity of cancer therapy, there is still lack of evidence-based approach for the monitoring and management of patients. This review will focus mainly on the recent advances in the molecular mechanisms of cardiotoxicity related to common cancer therapies while introducing the concept of cardio-oncology service. Applying the general principles of multi-disciplinary approaches toward the diagnosis, prevention, monitoring, and treatment of cancer therapy-induced cardiomyopathy and heart failure will also be discussed.
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10
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Report of two cases of acute cardiac adverse events in patients with colorectal carcinoma receiving oral capecitabine. Anticancer Drugs 2017; 28:801-807. [DOI: 10.1097/cad.0000000000000509] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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11
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Eason CT. Connections between rodenticides and drugs: a review of natural compounds with ecological, biocidal and medical applications. NEW ZEALAND JOURNAL OF ZOOLOGY 2017. [DOI: 10.1080/03014223.2017.1348956] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Charles T. Eason
- Faculty of Agriculture and Life Sciences, Department of Ecology, Lincoln University, Lincoln, New Zealand
- Cawthron Institute, Nelson, New Zealand
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12
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Hrynchak I, Sousa E, Pinto M, Costa VM. The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs. Drug Metab Rev 2017; 49:158-196. [DOI: 10.1080/03602532.2017.1316285] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Ivanna Hrynchak
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Emília Sousa
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
- CIIMAR – Centro Interdisciplinar de Investigação Marinha e Ambiental, Matosinhos, Portugal
| | - Madalena Pinto
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
- CIIMAR – Centro Interdisciplinar de Investigação Marinha e Ambiental, Matosinhos, Portugal
| | - Vera Marisa Costa
- Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, UCIBIO, REQUIMTE (Rede de Química e Tecnologia), Universidade do Porto, Porto, Portugal
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13
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Miura K, Shima H, Takebe N, Rhie J, Satoh K, Kakugawa Y, Satoh M, Kinouchi M, Yamamoto K, Hasegawa Y, Kawai M, Kanazawa K, Fujiya T, Unno M, Katakura R. Drug delivery of oral anti-cancer fluoropyrimidine agents. Expert Opin Drug Deliv 2017; 14:1355-1366. [PMID: 28379040 DOI: 10.1080/17425247.2017.1316260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules. Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs. Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.
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Affiliation(s)
- Koh Miura
- a Department of Surgery , Miyagi Cancer Center , Natori , Japan
| | - Hiroshi Shima
- b Division of Cancer Chemotherapy , Miyagi Cancer Center Research Institute , Natori , Japan
| | - Naoko Takebe
- c Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Investigational Drug Branch , National Institutes of Health, National Cancer Institute , Bethesda , MD , USA
| | - Julie Rhie
- d Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Regulatory Affairs Branch , National Institutes of Health, National Cancer Institute , Bethesda , MD , USA
| | - Kennichi Satoh
- e Miyagi Cancer Center Research Institute , Division of Cancer Stem Cell , Natori , Japan
| | - Yoichiro Kakugawa
- f Department of Breast Oncology , Miyagi Cancer Center , Natori , Japan
| | - Masayuki Satoh
- a Department of Surgery , Miyagi Cancer Center , Natori , Japan
| | - Makoto Kinouchi
- a Department of Surgery , Miyagi Cancer Center , Natori , Japan
| | | | | | - Masaaki Kawai
- f Department of Breast Oncology , Miyagi Cancer Center , Natori , Japan
| | | | - Tsuneaki Fujiya
- a Department of Surgery , Miyagi Cancer Center , Natori , Japan
| | - Michiaki Unno
- g Department of Surgery , Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Ryuichi Katakura
- h Department of Neurosurgery , Miyagi Cancer Center , Natori , Japan
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14
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Lischke J, Lang C, Sawodny O, Feuer R. Impairment of energy metabolism in cardiomyocytes caused by 5-FU catabolites can be compensated by administration of amino acids. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2016; 2015:5363-6. [PMID: 26737503 DOI: 10.1109/embc.2015.7319603] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Identification of patients with increased risk of 5-fluorouracil (5-FU)-related toxicity is an important challenge for cancer treatment. Research often focus on dihydropyrimidine dehydrogenase (DPYD) deficiency in this context. However, patients with normal DPYD activity may also develop life-threatening 5-FU adverse effects. DPYD initiates the catabolic route of 5-FU generating metabolites such as fluoroacetate (FAC). The catabolite FAC is known to inhibit the TCA cycle enzyme aconitase, which is supposed to impair mitochondrial energy metabolism. Therefore, we aim for a systems understanding of the association of 5-FU-related cardiac side effects with aconitase inhibition caused by FAC. Using a mitochondrial model of cardiomyocytes we found strong depletion of ATP production and citrate accumulation as main effects of aconitase inhibition. Shadow price analysis revealed that the uptakes of valine, arginine, proline and glutamate are most effective in compensating the impairment of energy metabolism. Our findings suggest that 5-FU catabolism contributes to the occurrence of cardiac adverse effects and are the basis for further biomarker identifications and development of side effect treatment.
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15
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Mahlberg R, Lorenzen S, Thuss-Patience P, Heinemann V, Pfeiffer P, Möhler M. New Perspectives in the Treatment of Advanced Gastric Cancer: S-1 as a Novel Oral 5-FU Therapy in Combination with Cisplatin. Chemotherapy 2016; 62:62-70. [PMID: 27643822 DOI: 10.1159/000443984] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 01/12/2016] [Indexed: 11/19/2022]
Abstract
Oral fluoropyrimidines have been available for more than 10 years. Capecitabine is well established in treating solid tumors in Europe. S-1 (Teysuno®), an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, has not been available in non-Asia countries until recently. In Japan, S-1 in combination with cisplatin is the recommended first-line treatment in patients with gastric cancer. In Europe, the first trials with S-1 were disappointing due to high unacceptable incidences of adverse events. Pharmacokinetic studies showed differences in Asian and Caucasian patients; therefore, a new non-Asian study program was initiated, which led to the pivotal phase 3 trial First-Line Advanced Gastric Cancer Study (FLAGS). In FLAGS, 1,053 patients with advanced gastric cancer from 24 non-Asian countries were enrolled. S-1 plus cisplatin showed no overall survival (OS) benefit when compared to 5-FU plus cisplatin. The primary endpoint superior OS was not met but better tolerability was shown. A post hoc noninferiority OS and safety analysis showed that S-1 plus cisplatin has the same efficacy as 5-FU plus cisplatin but a more favorable safety profile. This led to the approval of S-1 in combination with cisplatin in gastric cancer in Europe in 2011. This article reviews the mode of action of S-1, pivotal study results from an EU point of view, and future perspectives.
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Affiliation(s)
- Rolf Mahlberg
- First Department of Medicine, Mutterhaus der Borromäerinnen, Trier, Germany
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16
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Petrelli F, Barni S, Bertocchi P, Zaniboni A. TAS-102, the first "cardio-gentle" fluoropyrimidine in the colorectal cancer landscape? BMC Cancer 2016; 16:386. [PMID: 27377645 PMCID: PMC4932685 DOI: 10.1186/s12885-016-2409-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Accepted: 06/15/2016] [Indexed: 01/07/2023] Open
Abstract
Background Cardiotoxicity in the form of cardiac arrhythmia, myocardial infarction, and angina-like symptoms are not rare complications of fluoropyrimidines as 5-Fluorouracil (5FU) and capecitabine. Discussion Tas-102, a novel oral fluoropyrimidine, was recently approved by FDA for the treatment of advanced and refractory colorectal cancer. Its unique mechanism of action doesn’t seem linked with cardiotoxicity in clinical trials reported so far. Summary TAS 102 may represent one of the drugs of choice for patients with advanced colorectal cancer with cardiac disease. This intriguing and clinically relevant issue is briefly examined.
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Affiliation(s)
- Fausto Petrelli
- Department of Oncology, Division of Medical Oncology, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047, Treviglio, BG, Italy
| | - Sandro Barni
- Department of Oncology, Division of Medical Oncology, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047, Treviglio, BG, Italy
| | - Paola Bertocchi
- Oncology Department, Fondazione Poliambulanza, Via Bissolati 57, 25100, Brescia, Italy
| | - Alberto Zaniboni
- Oncology Department, Fondazione Poliambulanza, Via Bissolati 57, 25100, Brescia, Italy.
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17
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Gmeiner WH, Debinski W, Milligan C, Caudell D, Pardee TS. The applications of the novel polymeric fluoropyrimidine F10 in cancer treatment: current evidence. Future Oncol 2016; 12:2009-20. [PMID: 27279153 DOI: 10.2217/fon-2016-0091] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
F10 is a novel polymeric fluoropyrimidine drug candidate with strong anticancer activity in multiple preclinical models. F10 has strong potential for impacting cancer treatment because it displays high cytotoxicity toward proliferating malignant cells with minimal systemic toxicities thus providing an improved therapeutic window relative to traditional fluoropyrimidine drugs, such as 5-fluorouracil. F10 has a unique mechanism that involves dual targeting of thymidylate synthase and Top1. In this review, the authors provide an overview of the studies that revealed the novel aspects of F10's cytotoxic mechanism and summarize results obtained in preclinical models of acute myeloid leukemia, acute lymphocytic leukemia, glioblastoma and prostate cancer that demonstrate the strong potential of F10 to improve treatment outcomes.
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Affiliation(s)
- William H Gmeiner
- Wake Forest Baptist Medical Center Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Waldemar Debinski
- Wake Forest Baptist Medical Center Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Carol Milligan
- Wake Forest Baptist Medical Center Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Neurobiology & Anatomy, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - David Caudell
- Wake Forest Baptist Medical Center Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Timothy S Pardee
- Wake Forest Baptist Medical Center Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.,Department of Hematology/Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
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18
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Fakhri Y, Dalsgaard M, Nielsen D, Lav Madsen P. 5-Fluorouracil-induced acute reversible heart failure not explained by coronary spasms, myocarditis or takotsubo: lessons from MRI. BMJ Case Rep 2016; 2016:bcr-2015-213783. [PMID: 27251602 DOI: 10.1136/bcr-2015-213783] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
A 69-year-old woman presented with arterial hypotension, pulmonary oedema and a severely depressed left ventricular ejection fraction (LVEF) of 25% only 3 days after having received her first treatment for colorectal cancer with 5-fluorouracil (5-FU)-based therapy. The ECG demonstrated widespread ST-segment depression and echocardiography showed uniform hypokinesia of all left ventricular (LV) myocardial segments without signs of regional LV ballooning. Coronary angiography was normal and the patient gained full recovery after receiving treatment with heart failure medication. Interestingly, cardiac MRI scan 9 days later showed a normal LVEF with signs of neither myocardial oedema nor necrosis. Despite the high therapeutic efficacy of 5-FU in treatment of colorectal cancer, it is associated with undesired cardiac toxicities including coronary spasms, toxic inflammation and takotsubo cardiomyopathy. However, our patient did not fulfil the diagnostic criteria for the aforementioned complications. Based on this case report, we discuss alternative mechanisms including myocardial adenosine triphosphate depletion suggested from animal experiments.
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Affiliation(s)
- Yama Fakhri
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Department of Medicine, Division of Cardiology, Nykøbing F Hospital, Copenhagen University Hospital, Nykøbing F, Denmark
| | - Morten Dalsgaard
- Department of Cardiology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Dorte Nielsen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Per Lav Madsen
- Department of Cardiology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
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19
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Madeddu C, Deidda M, Piras A, Cadeddu C, Demurtas L, Puzzoni M, Piscopo G, Scartozzi M, Mercuro G. Pathophysiology of cardiotoxicity induced by nonanthracycline chemotherapy. J Cardiovasc Med (Hagerstown) 2016; 17 Suppl 1:e12-e18. [PMID: 27183520 DOI: 10.2459/jcm.0000000000000376] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The risk and mechanism of chemotherapy-induced cardiotoxicity (CTX) vary depending on the type and intensity of the anticancer regimen. Myriad chemotherapeutic drugs produce adverse cardiovascular effects such as arterial hypertension, heart failure, and thromboembolic events. Among the numerous classes of these drugs, anthracyclines have been studied most extensively because of their overt cardiovascular effects and the high associated incidence of heart failure. However, CTX might also be caused by other types of chemotherapeutic agents, including alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes). Here, we review the incidence, clinical impact, and potential mechanisms of CTX associated with nonanthracycline chemotherapy used for cancer patients. The published data support a marked increase in CTX risk, particularly with certain drugs such as 5-fluorouracil and cisplatin. Each anticancer regimen is associated with distinct modes of heart damage, both symptomatic and asymptomatic. However, the underlying mechanisms of CTX have been established only in a few cases, and only few nonanthracycline chemotherapeutics (mitoxantrone, mitomycin, ifosfamide) act through a recognizable mechanism and show a predictable dose dependence. Lastly, nonanthracycline chemotherapy can induce both chronic lesions, such as systolic dysfunction, and acute lesions, such as the ischemia that occurs within hours or days after treatment. An increased understanding of the incidence, mechanisms, and potential therapeutic targets of CTX induced by various nonanthracycline chemotherapeutic agents is clearly required.
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Affiliation(s)
- Clelia Madeddu
- aDepartment of Medical Sciences Mario Aresu, Unit of Medical Oncology bDepartment of Medical Sciences Mario Aresu, Unit of Cardiology and Angiology, University Hospital Cagliari, University of Cagliari, Cagliari cDivision of Cardiology, Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione Giovanni Pascale' - IRCCS, Naples, Italy
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20
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Amraotkar AR, Pachika A, Grubb KJ, DeFilippis AP. Rapid Extracorporeal Membrane Oxygenation Overcomes Fulminant Myocarditis Induced by 5‑Fluorouracil. Tex Heart Inst J 2016; 43:178-82. [PMID: 27127440 DOI: 10.14503/thij-15-5100] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Fulminant myocarditis is a rare but potentially life-threatening illness caused by 5-fluorouracil cardiotoxicity. Data supporting the use of extracorporeal membrane oxygenation for the treatment of fulminant myocarditis are limited. A 49-year-old, previously healthy white man, recently diagnosed with anal squamous cell carcinoma, developed severe chest pain hours after completing his first 96-hour intravenous 5-fluorouracil treatment. Over a period of 3 days from onset of symptoms, the patient developed cardiogenic shock secondary to fulminant myocarditis induced by 5-fluorouracil cardiotoxicity. This required emergency initiation of extracorporeal membrane oxygenation. The patient's systolic function recovered by day 5, and on the 17th day he was discharged in hemodynamically stable condition, without symptoms of heart failure. This case shows the importance of prompt recognition of cardiogenic shock secondary to 5-fluorouracil-induced myocarditis and how the immediate initiation of extracorporeal membrane oxygenation can restore adequate tissue perfusion, leading to myocardial recovery and ultimately the survival of the patient.
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21
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Abstract
Gastric cancer remains one of the most important malignancies worldwide in terms of incidence and mortality. The treatment is based on the combination of local surgery and radiation therapy as well as systemic chemotherapy and targeted molecules. Fluoropyrimidines and particularly 5-fluorouracil (FU) represent still the backbone for gastric cancer chemotherapy and new molecular versions of this molecule have been brought to clinical practice in order to improve benefits and reduce adverse effects. S-1 is an oral prodrug of 5-FU, which has demonstrated high effectiveness for gastric cancer treatment and a favorable safety profile. Currently, there are geographic differences in the treatment of gastric cancer and in the use of S-1, which is a mainstay of gastric cancer management in Eastern countries, but is not part of the standard care in the rest of the world. In this review, we gathered data from phase I, II, and III trials of S-1 in gastric cancer, in order to define its real benefit-risk ratio and assess whether geographic differences in S-1 use are justified by unchangeable factors.
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Affiliation(s)
- Eriseld Krasniqi
- Department of Systems Medicine, Medical Oncology, University of Rome 'Tor Vergata', Tor Vergata Clinical Center, Rome, Italy
| | - Stefania Pellicori
- Department of Systems Medicine, Medical Oncology, University of Rome 'Tor Vergata', Tor Vergata Clinical Center, Rome, Italy
| | - Vincenzo Formica
- Department of Systems Medicine, Medical Oncology, University of Rome 'Tor Vergata', Tor Vergata Clinical Center, Rome, Italy
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22
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Lai S, Marshall JL, Morrissey RL. Rechallenging 5-Fluorouracil in a Patient With Capecitabine-Induced Ventricular Fibrillation. Clin Colorectal Cancer 2015; 14:198-201. [DOI: 10.1016/j.clcc.2015.02.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 02/19/2015] [Accepted: 02/26/2015] [Indexed: 12/20/2022]
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23
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Polk A, Vistisen K, Vaage-Nilsen M, Nielsen DL. A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity. BMC Pharmacol Toxicol 2014; 15:47. [PMID: 25186061 PMCID: PMC4170068 DOI: 10.1186/2050-6511-15-47] [Citation(s) in RCA: 166] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Accepted: 08/19/2014] [Indexed: 12/29/2022] Open
Abstract
Background Cardiotoxicity is a serious side effect to treatment with 5-fluorouracil (5-FU), but the underlying mechanisms are not fully understood. The objective of this systematic review was to evaluate the pathophysiology of 5-FU- induced cardiotoxicity. Methods We systematically searched PubMed for articles in English using the search terms: 5-FU OR 5-fluorouracil OR capecitabine AND cardiotoxicity. Papers evaluating the pathophysiology of this cardiotoxicity were included. Results We identified 27 articles of 26 studies concerning the pathophysiology of 5-FU-induced cardiotoxicity. The studies demonstrated 5-FU-induced: hemorrhagic infarction, interstitial fibrosis and inflammatory reaction in the myocardium; damage of the arterial endothelium followed by platelet aggregation; increased myocardial energy metabolism and depletion of high energy phosphate compounds; increased superoxide anion levels and a reduced antioxidant capacity; vasoconstriction of arteries; changes in red blood cell (RBC) structure, function and metabolism; alterations in plasma levels of substances involved in coagulation and fibrinolysis and increased endothelin-1 levels and N-terminal-pro brain natriuretic peptide levels. Based on these findings the proposed mechanisms are: endothelial injury followed by thrombosis, increased metabolism leading to energy depletion and ischemia, oxidative stress causing cellular damage, coronary artery spasm leading to myocardial ischemia and diminished ability of RBCs to transfer oxygen resulting in myocardial ischemia. Conclusions There is no evidence for a single mechanism responsible for 5-FU-induced cardiotoxicity, and the underlying mechanisms might be multifactorial. Further research is needed to elucidate the pathogenesis of this side effect.
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Affiliation(s)
- Anne Polk
- Departments of Cardiology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
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24
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Endo A, Yoshida Y, Nakashima R, Takahashi N, Tanabe K. Capecitabine induces both cardiomyopathy and multifocal cerebral leukoencephalopathy. Int Heart J 2014; 54:417-20. [PMID: 24309454 DOI: 10.1536/ihj.54.417] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Chemotherapy for malignant tumors has diversified, and recognizing its side effects has become more important than ever. Both cardiotoxicity and neurotoxicity are rare, but they are among the most serious side effects caused by 5-fluorouracil (5-FU). Capecitabine is an orally administered prodrug that converts preferentially to 5-FU within tumors, resulting in enhanced concentrations of 5-FU in tumor tissue. Given that it targets tumor tissue, capecitabine was expected to reduce the risk of side effects associated with fluoropyrimidine. Here, we present the case of a 62-year-old man with colorectal adenocarcinoma who simultaneously experienced cardiomyopathy with cardiogenic shock and cerebral leukoencephalopathy during treatment with capecitabine. During emergency coronary angiography, ST-segment elevation and severely reduced left ventricular wall motion were observed; however, no severe coronary stenosis or spasm was revealed. Furthermore, we present a review of the literature on capecitabine-induced cardiotoxicity. As of April 2013, 39 case reports on capecitabine-induced cardiotoxicity have been published; however, cardiomyopathy was very rare, with only 3 cases reported. It is important for physicians to be aware of the various rare, but potentially serious, adverse effects associated with capecitabine chemotherapy and to inform patients about the possibility of these side effects, including cardiotoxicity and neurotoxicity.
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Affiliation(s)
- Akihiro Endo
- Division of Cardiology, Shimane University Faculty of Medicine
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25
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Alternative treatment options in colorectal cancer patients with 5-fluorouracil- or capecitabine-induced cardiotoxicity. Clin Colorectal Cancer 2012; 12:8-14. [PMID: 23102544 DOI: 10.1016/j.clcc.2012.09.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 09/09/2012] [Accepted: 09/13/2012] [Indexed: 02/07/2023]
Abstract
Most chemotherapy regimens in colorectal cancer treatment are 5-fluorouracil (5-FU)/leucovorin or capecitabine-based. Cardiotoxicity is a less common but potentially lethal complication of 5-FU or capecitabine treatment, and some physicians might be unfamiliar with treatment alternatives. Rechallenging should be avoided because it carries a high risk of recurrence of the cardiac symptoms and prophylactic treatment is not always protective. Possible alternative treatment options to be considered are to replace the oral capecitabine or intravenous 5-FU by a 5-FU bolus regimen, by uracil-tegafur or tegafur/gimeracil/oteracil, both oral fluoropyrimidines combining a 5-FU prodrug with a dihydropyrimidine dehydrogenase (DPD) inhibitor, or by raltitrexed, a thymidilate synthase inhibitor whose metabolism is independent of DPD. Patients with advanced colorectal cancer and fluoropyrimidine-induced cardiotoxicity can be treated with other non-fluoropyrimidine related chemotherapy, either as a single agent, combined, or in combination with biological agents. In this report we discuss the different alternative treatment options.
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26
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Sayre RS, Barr JW, Bailey EM. Accidental and experimentally induced 5-fluorouracil toxicity in dogs. J Vet Emerg Crit Care (San Antonio) 2012; 22:545-9. [PMID: 22817133 DOI: 10.1111/j.1476-4431.2012.00783.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Accepted: 06/11/2012] [Indexed: 12/01/2022]
Affiliation(s)
- Rebecca S. Sayre
- College of Veterinary Medicine; Texas A&M University; College Station; TX; 77843
| | - James W. Barr
- From the Departments of Small Animal Clinical Sciences; Texas A&M University; College Station; TX; 77843
| | - E. Murl Bailey
- Veterinary Physiology and Pharmacology; Texas A&M University; College Station; TX; 77843
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27
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Miura K, Shirasaka T, Yamaue H, Sasaki I. S-1 as a core anticancer fluoropyrimidine agent. Expert Opin Drug Deliv 2012; 9:273-86. [PMID: 22235991 DOI: 10.1517/17425247.2012.652945] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION 5-FU is a core anticancer agent for GI and other malignancies, and infusional 5-FU regimens have been widely utilized. Orally administrable fluoropyrimidine prodrugs have been developed to enhance the anticancer efficacy of 5-FU and to reduce its adverse reactions. AREAS COVERED S-1 is an FT-based oral 5-FU prodrug in combination with a DPD inhibitor (CDHP) and an OPRT inhibitor (Oxo), which exerts the following effects: i) maintaining normal gut immunity, Oxo can decrease GI toxicities of 5-FU; ii) sustaining high plasma 5-FU concentrations, Cmax of FBAL after S-1 administration is extremely low, which dramatically decreases adverse reactions such as HFS, neurotoxicities and cardiotoxicities; iii) plasma 5-FU concentrations vary less extensively after S-1 administration and iv) S-1 can be safely administered to patients with DPD deficiency. Furthermore, the alternate-day S-1 administration can reduce the GI toxicities and myelotoxicities of 5-FU without reducing its anticancer efficacy, enabling patients to continue the oral administration for 6 - 12 months. EXPERT OPINION Replacement of regimens with infusional 5-FU and other fluoropyrimidines by the alternate-day S-1 administration may be recommended because the latter procedure is efficient for patients while sustaining the enhanced anticancer efficacy of 5-FU and without reducing its dose intensity.
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Affiliation(s)
- Koh Miura
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
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28
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Yamane H, Matsubara M, Umemura S, Suwaki T, Kamei H, Takigawa N, Kiura K, Tanimoto M. Variant angina pectoris associated with FOLFOX4 therapy. World J Gastrointest Oncol 2011; 3:165-8. [PMID: 22110843 PMCID: PMC3220725 DOI: 10.4251/wjgo.v3.i11.165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Revised: 10/03/2011] [Accepted: 10/10/2011] [Indexed: 02/05/2023] Open
Abstract
The patient was a 71-year-old man who underwent a right hemicolectomy for ascending colon cancer (pT3, pN1, pM0) and who opted not to receive adjuvant chemotherapy. Eight months later, multiple liver metastases occurred. He therefore received FOLFOX4 (5-fluorouracil/leucovorin and 85 mg/m2 oxaliplatin) therapy, up to a total of 5 courses, and showed a partial response. While receiving the sixth course of FOLFOX4, he complained of chest pain and systemic itching approximately 15 min after the start of chemotherapy. An electrocardiogram revealed typical signs of ischemia. Coronary arteriography showed that the coronary arteries were intact. Believing the chest pain to be merely coincidental, we continued with the same therapy. However, he again developed the same chest pain during the seventh cycle of FOLFOX4 and treatment was stopped. We concluded that the patient’s symptoms were due to acute coronary syndrome (ACS) associated with the FOLFOX4 regimen. Variant angina as a type of ACS is a rare adverse effect of FOLFOX4. Clinicians should be aware of this potential adverse effect when monitoring patients receiving FOLFOX4.
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Affiliation(s)
- Hiromichi Yamane
- Hiromichi Yamane, Shigeki Umemura, Toshimitsu Suwaki, Haruhito Kamei, Division of Clinical Oncology, Sumitomo-Besshi Hospital Cancer Center, 3-1Ohji-cho, Niihama, Ehime 792-8543, Japan
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29
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Molteni LP, Cergnul M, Scaglietti U, Noonan DM, Bucci EO, Gottardi O, Albini A. Response to the Letter to the Editor. Breast J 2011. [DOI: 10.1111/j.1524-4741.2011.01126.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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30
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Ang C, Kornbluth M, Thirlwell MP, Rajan RD. Capecitabine-induced cardiotoxicity: case report and review of the literature. ACTA ACUST UNITED AC 2011; 17:59-63. [PMID: 20179805 PMCID: PMC2826779 DOI: 10.3747/co.v17i1.437] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Capecitabine, an oral prodrug of 5-fluorouracil (5fu), has been integrated into the management of multiple cancer types because of convenience of administration and efficacy comparable with 5fu. Cardiotoxicity induced by 5fu—in particular angina—has been well described in the literature, but reports of adverse cardiac events with capecitabine are also emerging. The mechanism underlying 5fu cardiotoxicity has long been thought to result from coronary vasospasm, but animal-model studies and patient echocardiographic findings both suggest a cardiomyopathic picture. Although 5fu cardiotoxicity is often reversible and can be managed supportively, presentations that are more severe—including arrhythmias, acute ischemic events, and cardiogenic shock—have been documented. In this report, we describe the case of a patient who ultimately required a pacemaker after developing symptomatic bradycardia and sinus arrest while receiving capecitabine for colon cancer.
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Affiliation(s)
- C Ang
- Department of Oncology, McGill University Health Centre, Montreal, QC
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31
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Karabay CY, Gecmen C, Aung SM, Guler A, Candan O, Batgerel U, Kalayci A, Kirma C. Is 5-fluorouracil-induced vasospasm a Kounis syndrome? A diagnostic challenge. Perfusion 2011; 26:542-5. [PMID: 21628340 DOI: 10.1177/0267659111410347] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Cardiovascular hypersensitivity is a rare and well-documented side-effect of 5-FU (5-fluorouracil). Besides the common complications such as angina pectoris and myocardial infarction, it can also cause cardiogenic shock, and supraventricular and ventricular arrhythmias. Studies have reported that FU-induced angina most commonly occurred due to vasospasm. In our case, 9 hours after stopping the infusion of 5-FU, the patients developed symptoms and electrocardiographic (ECG) findings consistent with acute myocardial infarction. We intend to share this rare case and discuss whether this late complication after 5-FU infusion is an FU-induced vasospasm or rather an allergic reaction leading to Kounis syndrome.
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Affiliation(s)
- C Y Karabay
- Kartal Koşuyolu Heart & Research Hospital, Cardiology Clinic, Istanbul, Turkey.
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32
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Jensen SA, Sørensen JB. 5-fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity. Cancer Chemother Pharmacol 2011; 69:57-64. [PMID: 21603868 DOI: 10.1007/s00280-011-1669-x] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2011] [Accepted: 05/03/2011] [Indexed: 01/26/2023]
Abstract
AIM This study aimed to elucidate the influence of 5-fluorouracil (5-FU)-based therapy on the vascular endothelium and its association with 5-FU-induced heart ischemia. METHODS The study prospectively accrued patients (n = 106) having completely resected colorectal cancer and receiving adjuvant treatment with 5-FU, folinic acid, and oxaliplatin. The levels of plasma von Willebrand factor (vWf), urine albumin-to-creatinine ratio (UACR), coagulation factor II + VII + X, and fibrin D-dimer were serially assessed before, during, and after chemotherapy. RESULTS The vWf level increased from median (range) 1.43 kU/l (0.48 to >3) to 2.64 kU/l (0.23 to >3) (P = 0.001), the UACR increased from 1.1 ± 0.2 mg/mmol (mean ± SE) to 2.1 ± 0.3 mg/mmol (P = 0.001), the coagulation factor II + VII + X activity decreased from 1.00 ± 0.02 to 0.94 ± 0.02 U/l (P = 0.001), and the fibrin D-dimer level increased from 1.1 ± 0.2 to 2.1 ± 0.3 kU/l (P = 0.001) at baseline and during chemotherapy, respectively. The changes in the levels of vWf (P = 0.3), UACR (P = 0.8), coagulation factor II + VII + X (P = 0.8), and fibrin D-dimer (P = 0.6) in nine (8.5%) patients having clinical signs of cardiotoxicity were not significantly different from that of the patients not having cardiotoxicity. The 5-FU-induced rise in plasma biomarkers was not significantly related to the cardiovascular morbidity or its risk factors (P = 0.9). CONCLUSIONS 5-FU therapy induces global reversible endothelial injury leading to a procoagulant state. The ensuing endothelial dysfunction may be of significance to the pathogenesis of 5-FU-induced clinically overt cardiotoxicity. Cardiovascular disease is not significant for the vulnerability of the endothelium to 5-FU-based chemotherapy.
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Affiliation(s)
- Søren Astrup Jensen
- Department of Oncology 5073, Rigshospitalet, Copenhagen University Hospital, 9 Blegdamsvej, 2100 Copenhagen, Denmark.
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33
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Killu A, Madhavan M, Prasad K, Prasad A. 5-fluorouracil induced pericarditis. BMJ Case Rep 2011; 2011:2011/apr15_1/bcr0220113883. [PMID: 22701028 DOI: 10.1136/bcr.02.2011.3883] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Cardiac toxicity is an infrequent, but potentially serious side effect of 5-fluorouracil (5-FU). The reported incidence of 5-FU-induced cardiotoxicity is approximately 3%, although estimates vary from 1.2% to 18%. Cardiac death occurs in less than 1%. The prompt recognition of cardiac toxicity demands a thorough understanding of the myriad of potential cardiac manifestations and a high index of suspicion. The most common presentation is angina pectoris while other manifestations, namely myocardial infarction, left ventricular dysfunction, arrhythmias and sudden death have been recognised. The authors report an unusual case of myopericarditis masquerading as myocardial infarction.
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Affiliation(s)
- Ammar Killu
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
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34
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Stewart T, Pavlakis N, Ward M. Cardiotoxicity with 5-fluorouracil and capecitabine: more than just vasospastic angina. Intern Med J 2011; 40:303-7. [PMID: 20529041 DOI: 10.1111/j.1445-5994.2009.02144.x] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In this case series we present a variety of different cardiac toxicities with 5-fluorouracil and its pro-drug capecitabine, including myocardial infarction, cardiomyopathy, sinoatrial and atrioventricular node dysfunction, takotsubo cardiomyopathy and QT prolongation with torsade-de pointes ventricular tachycardia. We stress the fact that while vasospasm is a well-recognized side-effect of this class of chemotherapeutic agent, broader cardiotoxicity is commonly seen and an increased awareness of the range of toxicity is necessary if repeat toxicity is to be avoided.
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Affiliation(s)
- T Stewart
- Department of Cardiology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
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Jensen SA, Hasbak P, Mortensen J, Sørensen JB. Fluorouracil Induces Myocardial Ischemia With Increases of Plasma Brain Natriuretic Peptide and Lactic Acid but Without Dysfunction of Left Ventricle. J Clin Oncol 2010; 28:5280-6. [DOI: 10.1200/jco.2009.27.3953] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose Fluorouracil (FU) is a cornerstone of colorectal cancer treatment; however, it has clinical and subclinical influence on the heart. This study aimed to clarify the pathophysiology, risk factors, and long-term effects of FU cardiotoxicity. Patients and Methods The study prospectively accrued colorectal cancer patients (n = 106) completely resected and adjuvantly treated with FU and oxaliplatin according to the FOLFOX4 regimen (infusional FU, folinic acid, and oxaliplatin). Serial measurements were made of systolic and diastolic features of the left ventricle by radionuclide ventriculography, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), lactic acid, and ECG before chemotherapy, immediately after a treatment infusion, and at follow-up 2 weeks after cessation of the intended 12 treatment courses and were further evaluated by multivariate regression analysis that included cardiovascular history and its risk factors. Results In the entire cohort, NT-proBNP significantly increased from baseline 14.5 ± 3.2 pmol/L (mean ± standard error) to 28.3 ± 5.3 pmol/L during FU therapy (P < .001). Nine patients (8.5%) with cardiotoxicity had significantly higher NT-proBNP of 55.3 ± 40.8 pmol/L compared with 25.4 ± 4.1 pmol/L in those without (P < .001). In multivariate analysis, the FU-induced rise of NT-proBNP was significantly higher in females (P < .001). Plasma lactic acid significantly increased from baseline (1.3 ± 0.1 mmol/L to 1.8 ± 0.1 mmol/L) during FU therapy (P < .001). Left ventricular ejection fraction at baseline of 0.66 ± 0.01 remained unchanged at 0.65 ± 0.01 during FU therapy and 0.66 ± 0.01 at follow-up (P = .4). Conclusion FU therapy generally induces myocardial neuroendocrine changes with increasing plasma NT-proBNP and lactic acid but without long-term dysfunction of the left ventricle. The usability of NT-proBNP as a predictive marker for FU cardiotoxicity remains to be clarified.
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Affiliation(s)
| | - Philip Hasbak
- From the Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Jann Mortensen
- From the Rigshospitalet, Copenhagen University Hospital, Denmark
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Miura K, Kinouchi M, Ishida K, Fujibuchi W, Naitoh T, Ogawa H, Ando T, Yazaki N, Watanabe K, Haneda S, Shibata C, Sasaki I. 5-fu metabolism in cancer and orally-administrable 5-fu drugs. Cancers (Basel) 2010; 2:1717-30. [PMID: 24281184 PMCID: PMC3837334 DOI: 10.3390/cancers2031717] [Citation(s) in RCA: 173] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Revised: 09/14/2010] [Accepted: 09/15/2010] [Indexed: 12/14/2022] Open
Abstract
5-Fluorouracil (5-FU) is a key anticancer drug that for its broad antitumor activity, as well as for its synergism with other anticancer drugs, has been used to treat various types of malignancies. In chemotherapeutic regimens, 5-FU has been combined with oxaliplatin, irinotecan and other drugs as a continuous intravenous infusion. Recent clinical chemotherapy studies have shown that several of the regimens with oral 5-FU drugs are not inferior compared to those involving continuous 5-FU infusion chemotherapy, and it is probable that in some regimens continuous 5-FU infusion can be replaced by oral 5-FU drugs. Historically, both the pharmaceutical industry and academia in Japan have been involved in the development of oral 5-FU drugs, and this review will focus on the current knowledge of 5-FU anabolism and catabolism, and the available information about the various orally-administrable 5-FU drugs, including UFT, S-1 and capecitabine. Clinical studies comparing the efficacy and adverse events of S-1 and capecitabine have been reported, and the accumulated results should be utilized to optimize the treatment of cancer patients. On the other hand, it is essential to elucidate the pharmacokinetic mechanism of each of the newly-developed drugs, to correctly select the drugs for each patient in the clinical setting, and to further develop optimized drug derivatives.
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Affiliation(s)
- Koh Miura
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; E-Mails: (M.K.); (H.O.); (T.A.); (N.Y.); (K.W.); (S.H.); (C.S.); (I.S.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +81-22-717-7205; Fax: +81-22-717-7209
| | - Makoto Kinouchi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; E-Mails: (M.K.); (H.O.); (T.A.); (N.Y.); (K.W.); (S.H.); (C.S.); (I.S.)
| | - Kazuyuki Ishida
- Department of Pathology, Tohoku University Hospital, Sendai, Japan; E-Mail:
| | - Wataru Fujibuchi
- Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan; E-Mail:
| | - Takeshi Naitoh
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; E-Mails: (M.K.); (H.O.); (T.A.); (N.Y.); (K.W.); (S.H.); (C.S.); (I.S.)
| | - Hitoshi Ogawa
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; E-Mails: (M.K.); (H.O.); (T.A.); (N.Y.); (K.W.); (S.H.); (C.S.); (I.S.)
| | - Toshinori Ando
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; E-Mails: (M.K.); (H.O.); (T.A.); (N.Y.); (K.W.); (S.H.); (C.S.); (I.S.)
| | - Nobuki Yazaki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; E-Mails: (M.K.); (H.O.); (T.A.); (N.Y.); (K.W.); (S.H.); (C.S.); (I.S.)
| | - Kazuhiro Watanabe
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; E-Mails: (M.K.); (H.O.); (T.A.); (N.Y.); (K.W.); (S.H.); (C.S.); (I.S.)
| | - Sho Haneda
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; E-Mails: (M.K.); (H.O.); (T.A.); (N.Y.); (K.W.); (S.H.); (C.S.); (I.S.)
| | - Chikashi Shibata
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; E-Mails: (M.K.); (H.O.); (T.A.); (N.Y.); (K.W.); (S.H.); (C.S.); (I.S.)
| | - Iwao Sasaki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; E-Mails: (M.K.); (H.O.); (T.A.); (N.Y.); (K.W.); (S.H.); (C.S.); (I.S.)
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Acute coronary syndrome associated with continuous 5-Fluorouracil infusion in a patient with metastatic colorectal cancer-a case report with a discussion on this clinical dilemma. J Gastrointest Cancer 2010. [PMID: 19936641 DOI: 10.1007/s12029-] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/29/2022]
Abstract
INTRODUCTION 5-Fluorouracil (5-FU) is considered to be the backbone of colorectal cancer (CRC) systemic therapy since the great majority of recommended regimens include its administration. A clinical picture consisting of chest pain, sometimes cardiac enzyme elevation, electrocardiogram abnormalities consistent with myocardial ischemia, and normal coronary angiogram associated with 5-FU administration have been infrequently reported. The clinical dilemma is: which chemotherapy regimen should we use in CRC patients with a previous acute coronary syndrome (ACS) associated with 5-FU? CASE REPORT We describe the case of a 55-year-old otherwise healthy woman with metastatic colon adenocarcinoma who presented an ACS probably secondary to arterial vasospasm while receiving continuous intravenous 5-FU infusion (mFOLFOX6 regimen). After the ACS, the patient was treated with raltitrexate plus oxaliplatin (TOMOX) and subsequently with irinotecan plus cetuximab with no other cardiac event. CONCLUSION The risk of cardiotoxicity associated with 5-FU is low but real. The probable mechanism is arterial vasospasm, as suggested by our case report. Both the use of the TOMOX regimen and irinotecan plus cetuximab seems to be safe regimens to be considered in this clinical scenario.
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Acute Coronary Syndrome Associated with Continuous 5-Fluorouracil Infusion in a Patient with Metastatic Colorectal Cancer—A Case Report with a Discussion on This Clinical Dilemma. J Gastrointest Cancer 2009; 40:133-7. [PMID: 19936641 DOI: 10.1007/s12029-009-9101-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Abstract
BACKGROUND The syndrome of 5-fluorouracil (5-FU)-associated cardiotoxicity remains poorly defined. PATIENTS AND METHODS We performed a literature review (1969 - 2007) and compiled data derived from 377 evaluable cases out of 448 reported cases. RESULTS Patient age ranged from 14 to 86 years. Of the patients 65% were 55 years old and the male:female ratio was 1.5:1. The most commonly treated tumors were gastrointestinal (60%), head and neck (22%) and breast (4%). Of the patients 14% had a history of heart disease whereas cardiac risk factors were found in 37%. Mode of administration included: continuous infusion (72%); bolus (22.5%); intermediate infusion (3%); oral (2%); and intraperitoneal (1 patient). The dosages of 5-FU used were < 750 mg/m(2)/day (36%), 751 - 999 (16%), 1,000 (26%), 1,001 - 1,499 (4%) and 1,500 (16%). Of the patients 54% received 5-FU in combination with other chemotherapeutic agents (cisplatin 44%) whereas 51% received 5-FU alone or with leucovorin. Only 4% patients had undergone previous or concomitant radiation therapy to the mediastinum. Of cardiac incidents that happened 69% were seen during or within 72 h of the first cycle of 5-FU. Angina occurred in 45% of patients whereas myocardial infarction was seen in 22%, arrhythmias in 23, acute pulmonary edema in 5, cardiac arrest and pericarditis in 1.4 and heart failure in 2. Electro-cardiographic evidence of ischemia or ST-T changes were recorded in 69% of patients, but abnormal cardiac enzymes were found in only 12%. The cardiac symptoms were reproducible in 47%, including in one patient subsequently treated with 5-FU p.o. Symptoms were also elicited when the same patients were treated with lower doses or different schedules. Of the patients 68% responded to conservative anti-anginal therapy, although prophylactic coronary vasodilators had limited efficacy. Overall, 8% of patients showing cardiotoxicity on 5-FU administration died. Furthermore, 13% reexposed to 5-FU died. CONCLUSIONS Our review suggests that 5-FU cardiotoxicity is an infrequent but real phenomenon that is independent of dose and may be related to a continuous infusion schedule. The presence of cardiac risk factors is not predictive. Patients should be observed closely and 5-FU administration discontinued if cardiac symptoms develop. A rechallenge with 5-FU should be reserved only for those patients in whom there is no reasonable alternative therapy and should be performed in the setting of aggressive prophylaxis and close monitoring.
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Affiliation(s)
- M Wasif Saif
- Yale University School of Medicine, FMP 116, CT 06520, New Haven, USA.
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Shirasaka T. Development history and concept of an oral anticancer agent S-1 (TS-1): its clinical usefulness and future vistas. Jpn J Clin Oncol 2008; 39:2-15. [PMID: 19052037 PMCID: PMC2639406 DOI: 10.1093/jjco/hyn127] [Citation(s) in RCA: 121] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Dushinsky et al. left a great gift to human beings with the discovery of 5-fluorouracil (5-FU). Approximately 50 years have elapsed from that discovery to the development of S-1 (TS-1®). The concept of developing an anticancer agent that simultaneously possesses both efficacy-enhancing and adverse reaction-reducing effects could be achieved only with a three-component combination drug. S-1 is an oral anticancer agent containing two biochemical modulators for 5-FU and tegafur (FT), a metabolically activated prodrug of 5-FU. The first modulator, 5-chloro-2,4-dihydroxypyridine (CDHP), enhances the pharmacological actions of 5-FU by potently inhibiting its degradation. The second modulator, potassium oxonate (Oxo), localizing in mucosal cells of the gastrointestinal (GI) tract after oral administration, reduces the incidence of GI toxicities by suppressing the activation of 5-FU in the GI tract. Thus, S-1 combines FT, CDHP and Oxo at a molar ratio of 1:0.4:1. In 1999–2007, S-1 was approved for the treatment of the following seven cancers: gastric, head and neck, colorectal, non-small cell lung, breast, pancreatic and biliary tract cancers. ‘S-1 and low-dose cisplatin therapy’ without provoking Grade 3 non-hematologic toxicities was proposed to enhance its clinical usefulness. Furthermore, ‘alternate-day S-1 regimen’ may improve the dosing schedule for 5-FU by utilizing its strongly time-dependent mode of action; the former is characterized by the low incidences of myelotoxicity and non-hematologic toxicities (e.g. ≤Grade 1 anorexia, fatigue, stomatitis, nausea, vomiting and taste alteration). These two approaches are considered to allow long-lasting therapy with S-1.
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Affiliation(s)
- Tetsuhiko Shirasaka
- Kitasato Institute for Life Science, Kitasato University, Shirogane, Tokyo, Japan.
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Martí V, Monell J, Seixo F, Falces C. Síndrome coronario agudo durante la monoterapia oral con capecitabina. Rev Esp Cardiol 2008. [DOI: 10.1157/13120005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Kosmas C, Kallistratos MS, Kopterides P, Syrios J, Skopelitis H, Mylonakis N, Karabelis A, Tsavaris N. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol 2007; 134:75-82. [PMID: 17636329 DOI: 10.1007/s00432-007-0250-9] [Citation(s) in RCA: 223] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2006] [Accepted: 05/29/2007] [Indexed: 10/23/2022]
Abstract
BACKGROUND Cardiotoxicity associated with 5-Fluorouracil (5FU) administration has been infrequently reported in literature, albeit various series of acute coronary syndromes have recorded a low but definite incidence of the above toxicity. In the present study, patients undergoing 5FU-based and oral capecitabine (Xeloda-based chemotherapy were tested for the potential development of cardiac-related symptoms during their administration. PATIENTS AND METHODS Six hundred and forty-four patients entered the study. Those experiencing any cardiac-related symptoms during 5FU infusion or oral capecitabine were subjected to ECG and serum cardiac enzymes determination. If cardiotoxicity was confirmed, 5FU infusion or oral capecitabine were interrupted, sublingual nitrates administered and cardiac monitoring initiated, while patients with >two-fold enzyme elevation were followed in a coronary care unit for at least 72 h. Cases with acute myocardial infarction were excluded from further 5FU or oral capecitabine treatment. RESULTS Overall 26 patients (4.03%) developed symptoms and/or ECG abnormalities due to 5FU and capecitabine. Patients with continuous 5FU infusion presented a higher incidence of cardiotoxicity [14/209; 6.7%, 95% confidence interval (CI) = 3.3-10.1%] than the remaining (7/317; 2.3%, 95% CI = 0.8-3.3%) (P < 0.012). Specifically, an increased incidence of cardiac-related events was encountered in patients with continuous 24-h 5FU + LV infusion for 5 days (12.5%, 95% CI = 2.3-22.7%) rather than in patients with the same schedule without LV (5.3%, 95% CI = 1.95-8.67%) (P < 0.027), as well as in patients with short 5FU + LV administration (2.4%, 95% CI = 0.9-3.9%) (P < 0.019). Overall, 3/54 patients (5.5%, 95% CI = -0.6-11.1%) on oral capecitabine developed cardiac-related events. Seven out of the 20 patients suffered an acute myocardial infarction, 6 developed ischemia only, while 4 more patients had ECG consistent with coronary vasospasm and 3 with conduction disturbances, of which one subsequently died. Patients administered oral capecitabine had a similar incidence of cardiac-related events; 1/22 (4.5%) patients with advanced breast cancer and 2/32 (6.2%) with colorectal cancer. CONCLUSIONS The present study supports the toxic effect of 5-FU on the myocardium, which is largely schedule-dependent, whereas a low but finite risk of such toxicity has been observed with oral capecitabine. A high level of alertness is required when using fluoropyrimidines (i.v. 5FU or oral capecitabine), while their toxic effect on the coronary endothelium and myocardium merits further investigation.
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Affiliation(s)
- Christos Kosmas
- Department of Medicine, 2nd Division of Medical Oncology, "Metaxa" Cancer Hospital, Piraues, 21 Apolloniou Street, 16341 Athens, Greece.
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Hrovatin E, Viel E, Lestuzzi C, Tartuferi L, Zardo F, Brieda M, Dametto E, Piazza R, Antonini-Canterin F, Vaccher E, Meneguzzo N, Nicolosi GL. Severe ventricular dysrhythmias and silent ischemia during infusion of the antimetabolite 5-fluorouracil and cis-platin. J Cardiovasc Med (Hagerstown) 2006; 7:637-40. [PMID: 16858245 DOI: 10.2459/01.jcm.0000237914.12915.dd] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The antimetabolite 5-fluorouracil is frequently used in the therapy of various malignancies. Cardiotoxicity has frequently been described during treatment, but there is no common agreement on the need to perform cardiovascular monitoring of patients during 5-fluorouracil administration. We report the case of a young patient with an head-neck cancer on whom a continuous electrocardiogram recording was performed, documenting serious ventricular dysrhythmias in the presence of myocardial ischemia during 5-fluorouracil and cis-platin infusion.
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Affiliation(s)
- Enzo Hrovatin
- UO Cardiologia-ARC, Dip. Emergenza, AO SM degli Angeli, Italy.
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Muneoka K, Shirai Y, Yokoyama N, Wakai T, Hatakeyama K. 5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine. Int J Clin Oncol 2006; 10:441-3. [PMID: 16369751 DOI: 10.1007/s10147-005-0516-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2005] [Accepted: 06/29/2005] [Indexed: 01/24/2023]
Abstract
Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of 5-FU into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity.
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Affiliation(s)
- Katsuki Muneoka
- Department of Surgery, Niitsu Medical Center Hospital, Niigata, Japan
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Jensen SA, Sørensen JB. Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol 2006; 58:487-93. [PMID: 16418875 DOI: 10.1007/s00280-005-0178-1] [Citation(s) in RCA: 151] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2005] [Accepted: 12/20/2005] [Indexed: 11/29/2022]
Abstract
AIM 5-fluorouracil (5-FU) and its prodrug capecitabine are cardiotoxic. This retrospective study aimed to identify risk factors and to give practical measures to make such chemotherapy feasible if cardiotoxicity occur. METHOD Review of cardiotoxicity among 668 patients treated with 5-FU or capecitabine for gastrointestinal cancers. RESULTS Cardiotoxicity occurred in 29 cases (4.3%). The number of cases according to cardiotoxicity CTC grades 2-4 for patients with and without pre-existing cardiovascular disease were none, 10, and 2 cases, and 3, 14, and no cases, respectively (P=0.16). In three patients intercurrent decrease of renal clearances to <30, 48 and 71 ml min(-1) led to markedly increased cardiotoxicity. Chemotherapy dose reduction to 70 or 50%, either alone or in addition to antiangina medication prevented cardiotoxicity during subsequent chemotherapy in nine (60%) and three (20%) cases out of 15 assessable patients (P=0.001), respectively. To abolish symptoms of cardiotoxicity, sublingual nitroglycerine was efficient for 15 patients and inefficient for two (P=0.001). CONCLUSION Cardiac and renal co-morbidity are risk factors for 5-FU induced cardiotoxicity. In this situation, rechallenge with modified 5-FU-based chemotherapy regimen supported by symptomatic medical treatment is feasible.
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Affiliation(s)
- Søren Astrup Jensen
- Department of Oncology 5073, National University Hospital, 9 Blegdamsvej, 2100, Copenhagen, Denmark.
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Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC. Cardiotoxicity of cancer therapy. J Clin Oncol 2005; 23:7685-96. [PMID: 16234530 DOI: 10.1200/jco.2005.08.789] [Citation(s) in RCA: 234] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Because cancer is a leading cause of mortality in the United States, the number of therapeutic modalities available for the treatment of neoplastic processes has increased. This has resulted in a large number of patients being exposed to a wide variety of cancer therapy. Historically, it has been well recognized that antineoplastic agents may have adverse effects on multiple organs and normal tissues. The most commonly associated toxicities occur in tissues composed of rapidly dividing cells and may spontaneously reverse with minimal long-term toxicity. However, the myocardium consists of cells that have limited regenerative capability, which may render the heart susceptible to permanent or transient adverse effects from chemotherapeutic agents. Such toxicity encompasses a heterogeneous group of disorders, ranging from relatively benign arrhythmias to potentially lethal conditions such as myocardial ischemia/infarction and cardiomyopathy. In some instances, the pathogenesis of these toxic effects has been elucidated, whereas in others the precise etiology remains unknown. We review herein the various syndromes of cardiac toxicity that are reported to be associated with antineoplastic agents and discuss their putative mechanisms and treatment.
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Affiliation(s)
- Justin D Floyd
- University of Missouri-Columbia, Ellis Fischel Cancer Center, 115 Business Loop 70 W, Columbia, MO 65203, USA
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Coward J, Maisey N, Cunningham D. The effects of capecitabine in Raynaud's disease: a case report. Ann Oncol 2005; 16:835-6. [PMID: 15788442 DOI: 10.1093/annonc/mdi144] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Lukaschek J, Nufer M, Maurer D, Asanger M, Honegger H, Widmer L, Malet-Martino M, Legay R, Martino R. Cardiotoxicity and neurotoxicity of high-dose continuous fluorouracil as a result of degradation compounds in the drug vials. J Clin Oncol 2005; 22:5022-5. [PMID: 15611524 DOI: 10.1200/jco.2004.04.272] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Kajita J, Fuse E, Kuwabara T, Kobayashi H. The Contribution of Cytochrome P450 to the Metabolism of Tegafur in Human Liver. Drug Metab Pharmacokinet 2003; 18:303-9. [PMID: 15618749 DOI: 10.2133/dmpk.18.303] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Fluorouracil (5-FU) prodrug tegafur (FT) is used widely for treating cancer patients. It has been reported that CYP2A6 and thymidine phosphorylase (TP) are involved in the formation of 5-FU from FT. In this study, the relative contribution of cytochrome P450 (P450) to the formation of 5-FU from FT was assessed using human liver 9000 x g supernatant (S9) and hepatocytes, which contain both enzymes. Intrinsic clearances of 5-FU formation from FT by P450 (NADPH dependent) and TP (NADPH independent) in human liver S9 were 1.36 and 0.169 microL/min/mg protein, respectively. The formation of 5-FU from FT in human liver S9 was inhibited over 82% by 8-methoxypsoralen, a CYP2A6-selective inhibitor. The formation of 5-FU from FT was also evaluated in human hepatocytes, cells that not only exhibit P450 and TP activity but also have anabolic capacity. The results indicated that CYP2A6 played a major role in 5-FU formation, which was consistent with the results using human liver S9. Factors that can affect the level of CYP2A6 activity in patients, e.g., genetic polymorphism, should be considered when using FT for chemotherapy.
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Affiliation(s)
- Jiro Kajita
- Pharmacokinetic Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Sunto-Gun, Shizuoka, Japan
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Frickhofen N, Beck FJ, Jung B, Fuhr HG, Andrasch H, Sigmund M. Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil. Ann Oncol 2002; 13:797-801. [PMID: 12075751 DOI: 10.1093/annonc/mdf035] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Capecitabine is a member of a new class of oral fluoropyrimidines. It is a 5-fluorouracil (5-FU) prodrug, activated by a series of enzymes. Activation has been demonstrated to occur preferentially in tumor tissue, which may explain the favorable balance of efficacy and toxicity of this drug. Cardiotoxicity, a rare but potentially serious adverse effect of 5-FU, has not been reported for capecitabine to date. Here we report a patient who experienced a severe and prolonged acute coronary syndrome during treatment with capecitabine. He had previously developed similar symptoms during treatment with infusional 5-FU. Capecitabine should thus be considered an agent with cardiotoxic potential. This adverse effect should be specifically monitored in all patients treated with capecitabine. Patients with symptoms suggestive of cardiotoxicity during previous treatment with a fluoropyrimidine should not be treated with capecitabine.
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Affiliation(s)
- N Frickhofen
- Department of Hematology/Oncology, HSK, Dr-Horst-Schmidt-Kliniken GmbH, Wiesbaden, Germany.
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