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

被引:35
作者
Cunha, KS
Reguly, ML
Graf, U
de Andrade, HHR
机构
[1] Univ Fed Rio Grande do Sul, Dept Genet, Lab Mutagenese, BR-91501970 Porto Alegre, RS, Brazil
[2] Univ Fed Goias, Dept Ciencias Fisiol, BR-74001970 Goiania, Go, Brazil
[3] Swiss Fed Inst Technol, Inst Toxicol, CH-8603 Schwerzenbach, Switzerland
关键词
D O I
10.1093/mutage/16.1.79
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 alpha,beta -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 study.
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页码:79 / 84
页数:6
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