5-fluorouracil induced cardiotoxicity: Review of the literature

Sorrentino, Michael F.; Kim, Jiwon; Foderaro, Andrew; Truesdell, Alexander G.

doi:10.5603/cj.2012.0084

Cited by 180 publications

(152 citation statements)

References 50 publications

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“…The functionality of the dual-organ platform was first validated using capecitabine, a prodrug that can undergo enzymatic activation by hepatocytes to the active form 5-fluorouracil (5-FU), which is a thymidylate synthase inhibitor thus inhibiting DNA synthesis (57). Once converted to 5-FU, it would exert increased cardiotoxicity compared to capecitabine (58). Indeed, we were able to reproduce such a process using our human heart-and-liver-on-chips platform (SI Appendix, Fig.…”

Section: Significancementioning

confidence: 99%

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Zhang

Aleman

Shin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

638

571

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Organ-on-a-chip systems are miniaturized microfluidic 3D human tissue and organ models designed to recapitulate the important biological and physiological parameters of their in vivo counterparts. They have recently emerged as a viable platform for personalized medicine and drug screening. These in vitro models, featuring biomimetic compositions, architectures, and functions, are expected to replace the conventional planar, static cell cultures and bridge the gap between the currently used preclinical animal models and the human body. Multiple organoid models may be further connected together through the microfluidics in a similar manner in which they are arranged in vivo, providing the capability to analyze multiorgan interactions. Although a wide variety of human organ-on-a-chip models have been created, there are limited efforts on the integration of multisensor systems. However, in situ continual measuring is critical in precise assessment of the microenvironment parameters and the dynamic responses of the organs to pharmaceutical compounds over extended periods of time. In addition, automated and noninvasive capability is strongly desired for long-term monitoring. Here, we report a fully integrated modular physical, biochemical, and optical sensing platform through a fluidics-routing breadboard, which operates organ-on-a-chip units in a continual, dynamic, and automated manner. We believe that this platform technology has paved a potential avenue to promote the performance of current organ-on-a-chip models in drug screening by integrating a multitude of real-time sensors to achieve automated in situ monitoring of biophysical and biochemical parameters.organ-on-a-chip | microbioreactor | electrochemical biosensor | physical sensor | drug screening D rug discovery is a lengthy process associated with tremendous cost and high failure rate (1). On average, less than 1 in 10 drug candidates are eventually approved by the Food and Drug Administration (2), during which successful transition ratios to next phases are roughly 65, 32, and 60% for phase I, phase II, and phase III, respectively (3). Among the primary causes of failure, nonclinical/ clinical safety (>50%) and efficacy (>10%) stand out in the front, more than all other factors (e.g., strategic, commercial, operational) combined (3, 4). These two major causes not only contribute to the low success rates during the drug development but also lead to the withdrawal of approved drugs from the market. Among all of the drug attritions, it is estimated that safety liabilities related to the cardiovascular system account for 45%, whereas 32% are due to hepatotoxicity (5, 6). These high failure/attrition ratios of drugs SignificanceMonitoring human organ-on-a-chip systems presents a significant challenge, where the capability of in situ continual monitoring of organ behaviors and their responses to pharmaceutical compounds over extended periods of time is critical in understanding the dynamics of drug effects and therefore accurate prediction of human organ reacti...

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Section: Significancementioning

confidence: 99%

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Zhang

Aleman

Shin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

638

571

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“…1,2 We show that prompt recognition of cardiogenic shock from fulminant myocarditis secondary to 5-FU cardiotoxicity-followed by the initiation of ECMO on an emergency basis-can provide adequate tissue perfusion and thereby an opportunity for myocardial recovery after discontinuation of 5-FU.…”

Section: Discussionmentioning

confidence: 99%

“…2,5 The exact mechanism is currently unclear, but the authors of a systematic review 5 have proposed multifactorial underlying causes, including endothelium-dependent and -independent pathways, direct myocardial damage from cytotoxic effects, induction of apoptosis, rheological side effects, and the production, during drug storage, of cardiotoxic metabolite precursors (for example, fluoro acetate). [6][7][8][9][10][11][12] Animal models of 5-FU cardiotoxicity have manifested apoptosis of myocytes, endothelial cells, or both, which gives rise to clinical presentations similar to that of myocarditis.…”

Section: Discussionmentioning

confidence: 99%

Rapid Extracorporeal Membrane Oxygenation Overcomes Fulminant Myocarditis Induced by 5‑Fluorouracil

Amraotkar¹,

Pachika²,

Grubb³

et al. 2016

Texas Heart Institute Journal

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Induced by 5-FluorouracilFulminant myocarditis is a rare but potentially life-threatening illness caused by 5-fluorouracil C hemotherapy regimens based on 5-fluorouracil (5-FU) are frequently administered in the treatment of gastrointestinal malignancies-especially colorectal carcinomas.1,2 Fulminant myocarditis is a rare but potentially life-threatening illness caused by 5-FU cardiotoxicity.3,4 Commonly presenting as chest pain, cardiac toxicity has manifestations that can include ischemic changes evident upon electrocardiography (ECG), and arrhythmias, myocardial infarction, heart failure, cardiogenic shock, and sudden death, with higher incidences in patients who have existing cardiac disease.5 Although salvage extracorporeal membrane oxygenation (ECMO) has been used successfully to treat various forms of cardiogenic shock, no data exist for the use of ECMO in the treatment of 5-FU-induced myocarditis. We report a case in which ECMO rescued a patient who was in cardiogenic shock resulting from 5-FU-associated fulminant myocarditis. Case ReportIn May 2014, a 49-year-old white man with newly diagnosed anal squamous cell carcinoma was being treated with combination therapy: radiotherapy, 5-FU, and mitomycin-C. At the start of chemotherapy, he had excellent exercise capacity and no history of cardiac disease to our knowledge. Hours after completing the first cycle of intravenous 5-FU treatment, the patient developed severe chest pain and presented at our emergency room.Upon arrival, the patient was alert, oriented, and hemodynamically stable, with a heart rate (HR) of 100 beats/min and a blood pressure (BP) of 100/70 mmHg. An ECG revealed diffuse ST-segment elevations (Fig. 1), and laboratory data included an elevated troponin I level (0.79 ng/mL). He was diagnosed with an ST-segmentelevation myocardial infarction and was transferred to the cardiac catheterization laboratory on an emergency basis.Coronary angiography revealed occlusion of the right coronary artery, which was well collateralized by the left anterior descending coronary artery (Fig. 2), and the Case Reports

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“…Th e therapy was discontinued and the patient was transferred to our intensive care unit because the electrocardiogram (ECG) showed ischemic changes. Th e fi rst ECG showed ST elevation and peaked T waves in D I-III , aVL, aVF and V [2][3][4][5][6] derivations as well as reciprocal changes in aVR and V I ( Figure 1). Detailed history revealed that a coronary angiography revealing non-pathological fi ndings was performed two weeks ago as a result of a similar clinical picture in another center.…”

Section: Case Presentationmentioning

confidence: 99%

“…It is frequently used in the treatment of gastrointestinal, breast, head and neck tumors and has cardiotoxic eff ects. Angina pectoris, acute myocardial infarction, supraventricular and ventricular tachycardia, coronary dissection, congestive heart failure, cardiomyopathy, myopericarditis, cardiogenic shock and sudden death are most serious cardiac side eff ects 1,2 . Th e frequency of cardiotoxicity is reported to be between 1.2-18% 3 .…”

Section: Introductionmentioning

confidence: 99%

A Case Of Coronary Vasospasm Due To 5-Fluorouracil Treatment: A Case Report

Tekiner¹,

Karakurt²,

Yıldız³

et al. 2015

Kafkas J Med Sci

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5-fluorouracil induced cardiotoxicity: Review of the literature

Abstract: 5-fluorouracil (5-FU) is a key chemotherapeutic agent in the treatment (Cardiol J 2012; 19, 5: 453-458)

Cited by 180 publications

References 50 publications

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Rapid Extracorporeal Membrane Oxygenation Overcomes Fulminant Myocarditis Induced by 5‑Fluorouracil

A Case Of Coronary Vasospasm Due To 5-Fluorouracil Treatment: A Case Report

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