Cardiotoxic effects of 5-fluorouracil in the guinea pig.

Matsubara, Issei; Kamiya, Joji; Imai, Shoichi

doi:10.1254/jjp.30.871

Cited by 100 publications

(47 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As the determination of the absolute level of the HEP is rather difficult, though not impossible, with the nuclear magnetic resonance technique, the effects of opening the thorax on myocardial energy metabolism were studied comparing the cardiotoxic effects of 5-fluorouracil in closed chest animals with those in open-chest animals. As reported in a previous paper, 5-FU is a compound which produces a depletion of HEP after a rather long latent period (1).…”

Section: Acceptedmentioning

confidence: 52%

31P-topical nuclear magnetic resonance (31P-TMR) studies of cardiotoxic effects of 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR).

et al. 1984

Self Cite

View full text Add to dashboard Cite

Abstract-Using the 31P-topical nuclear magnetic resonance method (TMR), an attempt was made to determine the myocardial high-energy phosphate compounds (HEP) contents under in situ conditions in closed-chest animals, and the effects of opening the thorax on the myocardial energy metabolism were studied comparing the cardiotoxic effects of 5-fluorouracil (5-FU) in closed-chest and open-chest animals.It was found that the depletion of myocardial HEP produced by 5-FU was much more marked in open-chest animals than in closed-chest ones, indicating the necessity of conducting the experiments in closed-chest animals for the proper evaluation of the cardiotoxicity of certain types of compounds. Therefore, the cardiotoxicity of a prodrug of 5-FU was assessed in closed-chest animals, and it was found to be less cardiotoxic than 5-FU.

show abstract

Section: Acceptedmentioning

confidence: 52%

31P-topical nuclear magnetic resonance (31P-TMR) studies of cardiotoxic effects of 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR).

et al. 1984

Self Cite

View full text Add to dashboard Cite

show abstract

“…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.…”

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

View full text Add to dashboard Cite

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

show abstract

“…Another hypothesis is 5-FU may have caused changes in membrane potential. Matsubara et al reported an excessive increase in the oxygen consumption and metabolite degeneration produced by the compound lead to the depletion of the high energy phosphate compound, which causes ECG change and chest symptom [6].…”

Section: Discussionmentioning

confidence: 99%

Successful Resuscitation from Cardiopulmonary Arrest: 5-FU Cardiotoxicity

Nakamura¹,

Kuwabara²,

Mitani³

et al. 2017

J Cardiovasc Dis Diagn

View full text Add to dashboard Cite

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.

show abstract

Cardiotoxic effects of 5-fluorouracil in the guinea pig.

Cited by 100 publications

References 11 publications

31P-topical nuclear magnetic resonance (31P-TMR) studies of cardiotoxic effects of 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR).

31P-topical nuclear magnetic resonance (31P-TMR) studies of cardiotoxic effects of 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR).

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

Successful Resuscitation from Cardiopulmonary Arrest: 5-FU Cardiotoxicity

Contact Info

Product

Resources

About