5-Fluorouracil-associated cardiotoxicity

Freeman, Nancy J.; Costanza, Mary E.

doi:10.1002/1097-0142(19880101)61:1<36::aid-cncr2820610108>3.0.co;2-6

Cited by 111 publications

(48 citation statements)

References 11 publications

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“…Systemic 5-FU concentrations have been measured to be 1 mM ¼ 0 . 13 mg/ml (Freeman & Costanza, 1988), which is in the range of the two lowest concentrations tested in this study and where no significant changes were observed. Thus generalized echinocytosis does probably not occur during treatment with 5-FU.…”

Section: Discussionmentioning

confidence: 65%

“…It is active against solid tumours such as cancer of the breast, gastrointestinal tract, head and neck, and in recent years the intravenous use of high doses (1000 mg/m 2 ) has been widely employed. Besides the wellknown toxic effects of 5-FU, namely myelosuppression, mucositis, diarrhoea, nausea and vomiting, unexplained cardiotoxicity has been observed (Anderson et al, 1993;Baker et al, 1986;De Forni et al, 1992;Freeman & Costanza, 1988;Misset et al, 1990;Robben et al, 1993). The incidence of cardiotoxicity ranges from 1% (Anderson et al, 1993) to 18% (Cwikiel et al, 1995) and probably depends on the dose and rate of 5-FU administration.…”

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confidence: 99%

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The anti‐neoplastic drug 5‐fluorouracil produces echinocytosis and affects blood rheology

Baerlocher¹,

Beer²,

Owen³

et al. 1997

Br J Haematol

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Summary. The anti-neoplastic agent 5-fluorouracil (5-FU) in high therapeutic doses can induce angina pectoris and myocardial infarction. The pathophysiological mechanism of this side-effect has not yet been elucidated. We analysed the influence of 5-FU on blood rheology in vitro. Whole blood, blood cell suspensions and plasma were incubated with increasing concentrations of 5-FU (final concentrations 0, 0 . 08, 0 . 4, 2, 10 and 25 mg/ml 5-FU) at 37ЊC. Erythrocyte morphology was analysed after fixation with glutaraldehyde. Viscosity was measured at high and low shear rates (94 and 0 . 1 s -1 ). Erythrocyte aggregation and the cell transit times of erythrocytes through 5 mm pores and polymorphonuclear leucocytes through 8 mm pores were determined. 5-FU induced a dose-dependent formation of echinocytes within minutes and was reversible upon removal of 5-FU, which reflected a preferential intercalation of the drug in the outer hemileaflet of the cell membrane. High shear blood viscosity was increased at the highest 5-FU concentration (148 Ϯ 12%), and at low shear rate a dose-dependent decrease was found (0 mg/ml: 100%, 0 . 08 mg/ml: 87 Ϯ 10%, 0 . 4 mg/ml: 80 Ϯ 19%, 2 mg/ml: 70 Ϯ 15%, 10 mg/ml: 40 Ϯ 19%, 25 mg/ml: 33 Ϯ 5%). Erythrocyte aggregation was decreased by the 5-FU-induced echinocytosis. The transit time of erythrocytes through narrow pores was increased in a dose-dependent manner by 5-FU, whereas the transit time of polymorphonuclear leucocytes was initially decreased at 10 mg/ml and returned to control after 60 min incubation. We conclude that 5-FU interacts with the cell membrane, induces echinocytosis and vesiculation and affects blood rheology in several ways which may contribute to cardiovascular complications.

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Section: Discussionmentioning

confidence: 65%

mentioning

confidence: 99%

The anti‐neoplastic drug 5‐fluorouracil produces echinocytosis and affects blood rheology

Baerlocher¹,

Beer²,

Owen³

et al. 1997

Br J Haematol

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“…Various hypotheses including ischemia secondary to coronary artery spasm, interaction of FU with the coagulation system, immunoallergic phenomena, direct toxicity of FU on the myocardium have been proposed to explain the cardiotoxicity of this drug (Freeman & Costanza, 1988;. However, the precise biochemical mechanism underlying this toxic side-effect still remains unknown even if the metabolic pathways of FU have now been largely elucidated (Heidelberger et al, 1983).…”

mentioning

confidence: 99%

Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug

Lemaire

Mc²,

Forni³

et al. 1992

Br J Cancer

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Summary The cardiotoxicity of 5-fluorouracil (FU) was attributed to impurities present in the injected vials. One of these impurities was identified as fluoroacetaldehyde which is metabolised by isolated perfused rabbit hearts into fluoroacetate (FAC), a highly cardiotoxic compound. FAC was also detected in the urine of patients treated with FU. These impurities were found to be degradation products of FU that . However, the precise biochemical mechanism underlying this toxic side-effect still remains unknown even if the metabolic pathways of FU have now been largely elucidated (Heidelberger et al., 1983). The cytotoxic activity of this drug stems from the anabolic pathway that leads to fluoronucleosides (FNUCs) then fluoronucleotides (FNUCt). The degradative pathway of FU biotransformation is called the catabolic pathway and mainly leads to a-fluoro-p-alanine (FBAL), an a-fluoro-13-amino-acid which closely resembles the natural P-amino-acid, 0-alanine. P-alanine is converted into acetate which enters the Krebs cycle and undergoes a metabolic conversion to citrate. By analogy with the natural substrate, it has been suggested but never demonstrated that FBAL might be transformed into fluoroacetate (FAC) (Philips et al., 1959;Koenig & Patel, 1970;Matsubara et al., 1980). FAC is known to be a highly cardiotoxic and neurotoxic poison. Indeed, it also enters the Krebs cycle, is then transformed into fluorocitrate (FC) which inhibits citrate metabolism resulting in accumulation of intracellular citrate (Pattison & Peters, 1966) (Figure 1).Having at our disposal a powerful method for studying the metabolism of fluorinated drugs, especially fluoropyrimidines (Malet-Martino et al., 1990), we explored the possibility of a direct toxic effect of FU or one of its metabolites on the mycocardium using fluorine-19 nuclear magnetic resonance ('9F NMR) and the isolated perfused rabbbit heart (IPRH) model. We also report in this paper the results of the '9F NMR analysis of biofluids from patients treated with FU. We demonstrate that a degradation compound of FU, resulting from the storage of this drug in alkaline conditions and found in the injected vials, is responsible for the cardiotoxicity of this antineoplastic drug since it is metabolised into FAC. Materials and methods MaterialsCommercial FU Roche vials from France (50 mg FU ml-' of an aqueous solution buffered with Tris, pH = 8.5), Germany (25 mg FU ml-' of an aqueous NaOH solution, pH = 8.5), Great Britain (25 mg FU ml-I of an aqueous NaOH solution, pH = 8.5), USA (50 mg FU ml-of an aqueous NaOH solution, pH = 9.2) and a commercial US generic from SoloPak Laboratories (50 mg FU ml-' of an aqueous NaOH solution, pH = 9

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“…There are some well-known adverse effects of 5-FU and cardiotoxicity is one of them. Reported cardiovascular events include chest pain, dyspnea, confusion, ECG changes, vasospastic myocardial ischemia, myocardial infarction, and sudden death [1]. In terms of 5-FU induced cardiovascular toxicities, the incidence and mortality varies depending on the study.…”

Section: Discussionmentioning

confidence: 99%

“…Continuous 5-FU infusion and/or combination therapy with cisplatin is associated with a higher incidence of cardiotoxicity [7]. Leucovorin plus continuous 5-FU infusion also increases the rate of cardiotoxicity compared with 5-FU alone [1]. Pharmacokinetics of 5-FU can be an important factor to the cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Successful Resuscitation from Cardiopulmonary Arrest: 5-FU Cardiotoxicity

Nakamura¹,

Kuwabara²,

Mitani³

et al. 2017

J Cardiovasc Dis Diagn

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A 61-year-old man with 5-fluorouracil (5-FU) chemotherapy suffered a cardiopulmonary arrest (CPA). The electrocardiogram showed changes consistent with myocardial infarction only during CPA that was normalized 30 minutes after cardiopulmonary resuscitation. Coronary angiography showed no significant stenosis. We suspected the cause of CPA to be vasospastic angina due to 5-FU and administered Benidipine, Diltiazem, and Isosorbide mononitrate to prevent recurrence of vasospasm.

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5-Fluorouracil-associated cardiotoxicity

Cited by 111 publications

References 11 publications

The anti‐neoplastic drug 5‐fluorouracil produces echinocytosis and affects blood rheology

The anti‐neoplastic drug 5‐fluorouracil produces echinocytosis and affects blood rheology

Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug

Successful Resuscitation from Cardiopulmonary Arrest: 5-FU Cardiotoxicity

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