Abstract
From a mutagenized population of wildtype Leishmania donovani promastigotes, clonal isolates of mutant organisms were isolated in semi-solid agar containing 200μM 5-fluorouracil. These mutant organisms were cross-resistant to the cytotoxic effects of 5-fluorouridine but were just as sensitive to 5-fluorodeoxyuridine and methotrexate. Wildtype and mutant organisms, however, were equally capable of accumulating radiolabelled 5-fluorouracil, uracil, and uridine into anionic metabolites, suggesting a lack of a metabolic defect in the mutant organisms. Measurements of the intracellular nucleoside triphosphate levels did not indicate any abnormalities. Yet overnite incubations of wildtype cells with cytotoxic (50μM) concentrations of 5-fluorouracil markedly depleted pyrimidine nucleoside triphosphate pools without affecting ATP and GTP levels. In mutant organisms no such depletion of CTP and UTP were observed after similar incubations with 5-fluorouracil. Certain naturally occurring pyrimidines could protect wildtype cells from the cytotoxic effects of 5-fluorouracil. This biochemical genetic analysis of 5-fluorouracil-resistant Leishmania donovani suggests that 5-fluorouracil exerts its cytotoxic effects by inhibiting pyrimidine biosynthesis and that the mutant cells possess a genetically altered pyrimidine biosynthetic pathway.
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Kaur, K., Ullman, B. ISOLATION AND CHARACTERIZATION OF LEISHMANIA DONOVANI RESISTANT TO 5-FLUOROPYRIMIDINES: 100. Pediatr Res 19, 760 (1985). https://doi.org/10.1203/00006450-198507000-00120
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DOI: https://doi.org/10.1203/00006450-198507000-00120
