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 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.
Cunha
K S
KS
Departamento de Ciências Fisiológicas, Universidade Federal de Goiás, CP 131, 74001-970 Goiânia, GO, Brasil.
Reguly
M L
ML
Graf
U
U
de Andrade
H H
HH
D020533:Angiogenesis Inhibitors / Q000633:toxicity; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D001711:Biotransformation / Q000187:drug effects / Q000235:genetics; D001952:Bridged-Ring Compounds / Q000633:toxicity*; D000077143:Docetaxel; D004331:Drosophila melanogaster / Q000166:cytology / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000187:drug effects; D007814:Larva / Q000187:drug effects / Q000235:genetics; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000633:toxicity; D043823:Taxoids
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D005819:Genetic Markers; D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D000077143:Docetaxel; C080625:taxane; D017239:Paclitaxel