Genotoxidade de alcalóide camptotecina e do seu análogo irinotecan através do ciclo parassexual em Aspergillus nidulans (teleomorfo Emericella nidulans)

Abstract

Mitotic recombination is an important mechanism involved in carcinogenesis which can lead to genetic loss by LOH, when the recombinant sister chromatids segregate in mitosis to different daughter cells. The recombinogenic potential of two antineoplastic agents, previously characterized as DNA-topoisomerase I inhibitors, camptothecin (CPT) and irinotecan (CPT-11), was evaluated in the present study. The homozygotization assay, which assess the induction of mitotic recombination and gene homozygosis, as well as the heterozygous A757//UT448 diploid strain of Aspergillus nidulans were employed. Three non-cytotoxic concentrations of CPT (3.5 ng ml-1, 10.5 ng ml-1 and 17.4 ng ml-1) were found to induce both mitotic recombination and gene homozygosis in treated A. nidulans diploid cells. CPT treatment produced three diploids homozygous, for nutritional and conidia color genes, and Homozygotization Indices (HI) significantly (p<0.05) different from negative control. On the other hand, with concentratios of CPT-11 (18 μg ml-1, 9 μg ml-1 e 4,5μg ml-1) only the highest CPT-11 concentration tested, corresponding to the maximal single chemotherapeutic dose, produced HI values higher than 2.0 and significantly different from negative control HI values. The recombinogenic effects of both topoisomerase I blockers were associated with the recombinational repair of DNA strand breaks induced by CPT and CPT-11.