Comparison of camptothecin derivatives presently in clinical trials: genotoxic potency and mitotic recombination

The genotoxicity of camptothecin (CPT) and its clinical antineoplastic analogues irinotecan (CPT-11) and topotecan (TPT) were evaluated using the wing somatic mutation and recombination test (SMART) in Drosophila melanogaster. These compounds stabilize and trap the topoisomerase I-DNA complex, preventing the religation step of the breakage/rejoining reaction mediated by the enzyme. The standard version of the wing SMART was used to evaluate the three compounds and to compare the wing spots induced in marker-heterozygous and balancer-heterozygous flies. The results demonstrate that all compounds tested have a significant genotoxic effect in both genotypes analysed. At the same time, a comparison of the clone induction frequencies in marker-heterozygous and balancerheterozygous flies shows that mitotic recombination is the prevalent mechanism through which the three compounds induce all categories of wing spots (78-93% recombination). TPT was the most genotoxic compound, probably because substitutions of amino groups for the 9-carbon of the CPT A ring leads to compounds with greater in vivo activity. CPT and CPT-11 induced, respectively, about 7 and 28 times fewer mutant clones per millimolar exposure unit than TP

Comparison of camptothecin derivatives presently in clinical trials: genotoxic potency and mitotic recombination

ISSN:0267-8357ISSN:1464-380

Taxanes: the genetic toxicity of paclitaxel and docetaxel in somatic cells of Drosophila melanogaster

In this study, the taxanes, paclitaxel and docetaxel were investigated for genotoxicity in the wing spot test of Drosophila melanogaster. These relatively new drugs are used in cancer therapy and show great promise in the treatment of a variety of cancers. Their major cellular target is the α,β-tubulin dimer but, unlike other spindle poisons, they stabilize microtubules by a shift towards assembly, producing nonfunctional microtubule bundles. The Drosophila wing Somatic Mutation and Recombination Test (SMART) provides a rapid means to evaluate agents able to induce gene mutations and chromosome aberrations, as well as rearrangements related to mitotic recombination. We applied the standard version of SMART (with normal bioactivation) and a variant version with increased cytochrome P450-dependent biotransformation capacity. In the standard assay, docetaxel was found to be aneuploidogenic; this was effectively abolished by a high cytochrome P450-dependent detoxification capacity. This suggests, as previously reported, the involvement of this family of enzymes in the detoxification of docetaxel rather than in its activation. In contrast, paclitaxel was clearly non-genotoxic at the same (millimolar) concentrations as used for docetaxel in both crosses. The weak responsiveness of SMART assays to aneugenic compounds, the weaker ligand and assembly action of paclitaxel and the more rapid reversibility of the microtubules formed with this compound, may have caused the negative response observed in the present stud

Taxanes: the genetic toxicity of paclitaxel and docetaxel in somatic cells of Drosophila melanogaster

ISSN:0267-8357ISSN:1464-380

Avaliação comparativa dos efeitos tóxico-genéticos da própolis em células somáticas de Drosophila melanogaster, portadoras de diferentes níveis de enzimas de metabolização

O objetivo deste estudo foi avaliar a atividade genotóxica e anticitotóxica da própolis sobre as lesões induzidas por mitomicina C (MMC) utilizando linhagens de Drosophila melanogaster portadoras de diferentes níveis de expressão de enzimas de metabolização do tipo citocromo P-450. Empregou-se o Teste para Detecção de Mutação e Recombinação em Células Somáticas de asas de D. melanogaster (SMART), que fornece grande espectro de informações sobre a detecção de mutações gênicas, cromossômicas e/ou recombinações genéticas. Os resultados obtidos indicaram que a própolis atuou como modulador direto dos efeitos citotóxicos induzidos pela MMC. Além disso, demonstrou-se que a própolis não induziu eventos mutagênicos e/ou recombinogênicos em células somáticas de D. melanogaster. O conjunto de dados apresentados neste trabalho corrobora aqueles descritos na literatura, contribuindo para que se determine o nível de atividade protetora exercida pela própolis quando administrada juntamente com agentes genotóxicos que apresentam diferentes mecanismos de ação