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

Departamento de Ciências Fisiológicas, Universidade Federal de Goiás, CP 131, 74001-970 Goiânia, GO, Brasil.
Mutagenesis (Impact Factor: 3.5). 02/2001; 16(1):79-84. DOI: 10.1093/mutage/16.1.79
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ABSTRACT 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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    • "In another report, PAC significantly increased the micronucleated rates in a concentration-dependant manner in healthy human lymphocytes (Digue et al., 2002). In contrast to those in vitro results, Cunha et al. (2001) reported that paclitaxel was non-genotoxic in Drosophila wing somatic mutation and recombination test (SMART). However, PAC appeared as cytotoxic clastogene in mouse lymphoma cells by using comet and apoptotic assays (Lee et al., 2003). "
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    • "Genotoxicity evaluation employed a two-fold rule where positive identification of genetic toxicity requires a total spot response two-fold greater than the negative control, without the requirement of a clear concentration–response relationship (Cunha et al., 2001; Tiburi et al., 2002). The recombinagenic action of the drugs was calculated by comparing the clone induction frenquencies per 10 5 cells per cell division obtained from mwh/flr 3 and mwh/TM3 genotypes (Frei and Würgler, 1996) . "
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    • "In another report, PAC significantly increased the micronucleated rates in a concentration-dependant manner in healthy human lymphocytes (Digue et al., 2002). In contrast to those in vitro results, Cunha et al. (2001) reported that paclitaxel was non-genotoxic in Drosophila wing somatic mutation and recombination test (SMART). However, PAC appeared as cytotoxic clastogene in mouse lymphoma cells by using comet and apoptotic assays (Lee et al., 2003). "
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