Metronidazole (Flagyl): iron catalysed reaction with sulphydryl groups and tumour radiosensitisation.

Abstract

THE possibility of using hypoxic cell radiosensitising drugs as adjuncts in the radiotherapy of some forms of cancer has received renewed attention1–4. In particular administration of metronidazole (Flagyl, May and Baker Ltd) to tumour bearing mice before exposure to X rays, has been found to reduce the radiation dose required to control 50% of the tumours by a factor of 1.2–1.3 (refs 5 and 6). Preliminary clinical trials are now in progress7. The drug was originally chosen for study because of its constituent nitro group (which suggested it was a strong radical oxidant) and its extremely favourable pharmacological and toxicological properties8. Previously the activity of a large number of radiosensitisers had been attributed to their ability to react with intracellular sulphydryl compounds9,10. The ability of the cell to repair radiation-induced free radical lesions by hydrogen11 or electron donation12 would thus be lowered. Measurements13 of anoxic solutions over a period of 2 h did not, however, show any appreciable reaction between metronidazole (8 × 10−4 M) and the sulphydryl groups of cysteamine (8 ×10−4 M) or dithiothreitol (4 ×10−4 M). Recent associated pharmacological studies with rat intestinal contents have prompted us to re-examine the reaction of metronidazole with sulphydryl compounds and to investigate the possibility of catalysis by ferrous ions. We now report experiments which show that the drug reacts with an iron–cysteine complex over time scales of the order of a second. A drug–iron–cysteine complex is formed which is subsequently reduced over a period of minutes.