Cytotoxic and genotoxic effects of megazol, an anti-Chagas’ disease drug, assessed by different short-term tests

Abstract

Cyto- and genotoxicity induced by drugs can limit the dose and duration of treatment, can adversely affect patient quality of life, and may be life-threatening. Two drugs are currently being used for treatment of the acute phase of Chagas’ disease and both have serious undesirable effects. In this research, cyto- and genotoxic activity of the nitroimidazole-tiadiazole derivative CL 64855 2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole (megazol), a promising alternative drug, was evaluated in vitro with different short-term tests: (a) induction of recombination events and mutation in the yeast Saccharomyces cerevisiae D7 strain, with and without induction of cytochrome P-450; DNA damage (single and double strand breaks, alkali-labile sites, etc.) by the Comet assay in different mammalian cells. S. cerevisiae did not show a significant increase of mutant and recombinant event frequency, both with and without cytochrome P-450. On the other hand, the cytochrome complex appeared to detoxify the drug with respect to cytotoxicity. Results in rat and mouse fresh leukocytes showed a dose–response relation of drug-induced DNA damage. Findings in treated VERO cells suggested a complex treatment time–DNA damage relationship and the possible induction of repair mechanisms. Furthermore, bleomycin effects were increased in rat cells by simultaneous administration of megazol. Megazol shows different biological activity in relation to cellular types and experimental conditions (with or without cytochrome P-450, short/long time of exposure, with or without other genotoxins), thus suggesting a modulation of effectiveness by different physiological/biochemical conditions of cells. The findings could be useful to evaluate new megazol-derived compounds and to assess the risks/benefits relationship for each drug.