Fluorouracil Cardiotoxicity

Abstract

Fluorouracil cardiotoxicity may be much more common and clinically significant than previously thought. A high index of suspicion for cardiotoxicity must be maintained when the drug is administered, especially in the presence of heart disease and concomitant radiation therapy. In the presence of chest pain, it is mandatory to stop the infusion and, if possible, to replace fluorouracil with another chemotherapeutic agent.

The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate

“…FBAL may well be further metabolized in these tissues over long periods of time. These observations could account for the delayed onset of cardiotoxic or neurotoxic symptoms with respect to the beginning of treatment in patients receiving FU (Moore et al, 1990;Anand, 1994).…”

“…Its chief side-effects are myelosuppression, diarrhoea, vomiting and mucositis. However, over the last decade, the number of reports of cardiotoxicity and neurotoxicity attributed to FU has rapidly increased, probably because of the use of higher doses in continuous perfusion (Moertel et al, 1964;Rezkalla et al, 1989;Moore et al, 1990;Gamelin et al, 1991; De Fomi et al, 1992;Robben et al, 1993;Anand, 1994). The precise biochemical mechanism underlying these two side-effects remains unclear, although several investigators have postulated, but never demonstrated experimentally, that FU might be transformed into fluoroacetate (FAC), a highly cardiotoxic and neurotoxic poison (Koenig and Patel, 1970;Okeda et al, 1990).…”

Traditional and novel methods to assess and prevent chemotherapy-related cardiac dysfunction noninvasively

“…Cardiotoxicity has been reported in up to 2.3% of patients receiving 5-fluorouracil. 24 Coronary vasospasm associated with 5-fluorouracil is associated with ischemia, chest pain, ECG repolarization changes, myocardial infarction, and death. Prospective study of 100 consecutive patients without cardiac history or abnormal ECG at baseline showed 8 patients (8%) developed chest pain, ECG changes, and one case of cardiogenic shock within 18-30 hours of the initiation of the high-dose 5-fluorouracil infusion.…”

5-Ethynyluracil (GW776): effects on the formation of the toxic catabolites of 5-fluorouracil, fluoroacetate and fluorohydroxypropionic acid in the isolated perfused rat liver model

“…Common clinical adverse reactions include myelosuppression, diarrhoea, vomiting and mucositis. Over the last decade, the number of reports of cardiotoxicity and neurotoxicity attributed to 5-FU has rapidly increased (Anand, 1994;Yeh and Cheng, 1994; and references cited therein). The biochemical mechanism underlying these toxic side-effects remains unclear, although it has been postulated that 5-FU, and more precisely its main catabolite ex-fluoro-p-alanine (FBAL) (Mukherjee and Heidelberger, 1960;Bemadou et al, 1985; Heggie et al, 1987; Hull et al, 1988), might be transformed into fluoroacetate (FAC) (Koenig and Patel, 1970), a highly cardiotoxic and neurotoxic poison (Pattison and Peters, 1966).…”