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

Abstract

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

Raltitrexed (Tomudex): an alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity

“…Several causative mechanisms for 5-FU cardiotoxicity have been postulated, including an autoimmune response to damaged cells (Stevenson et al, 1977), increased oxygen demand in patients receiving 5-FU (Rezkalla et al, 1989), coronary spasm (Burger and Mannino, 1987) due to protein kinase C-mediated vasoconstriction (Mosseri et al, 1993) and the 5-FU contaminant fluoroacetate (FAC) (Lemaire et al, 1992).…”

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

“…Moreover, the dry powder of orally formulated 5-FU presents the advantage of being devoid of cardiotoxic breakdown products found in i.v. solutions (Lemaire et al, 1992). This combination is currently in intemational phase II clinical trials for breast, pancreatic, colorectal and hepatocellular cancer.…”

“…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). We demonstrated on the isolated perfused rabbit heart model that commercial solutions of 5-FU contain cardiotoxic impurities, namely fluoromalonic acid semialdehyde (FMASAld) and fluoroacetaldehyde (Facet), that are derived from the degradation of 5-FU in the basic medium required for its solubilization and are metabolized into FAC and 2-fluoro-3-hydroxypropionic acid (FHPA), another cardiotoxic compound (Lemaire et al, 1992(Lemaire et al, , 1994. Moreover, we were the first to demonstrate experimentally the biotransformation of pure 5-FU into two new catabolites, FAC and FHPA, in the isolated perfused rat liver (IPRL) model and in rats (Arellano et al, 1994).…”

Raltitrexed induces mitochondrial-mediated apoptosis in SGC7901 human gastric cancer cells

“…Cardiac toxicity induced by 5-FU is a less common, although significant and potentially lethal side-effect. Unlike 5-FU, raltitrexed does not cause the accumulation of associated metabolites, which increase cardiotoxicity (13,14). Based on preliminary clinical observations, survival benefits were achieved in certain advanced gastric cancer patients receiving raltitrexed either alone or in combination with other therapeutic agents, such as paclitaxel and docetaxel.…”