Taxanes: the genetic toxicity of paclitaxel and docetaxel in somatic cells of Drosophila melanogaster.
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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ABSTRACT: A Mandevilla velutina crude extract was investigated using the mouse micronucleus test (MNT) and the Drosophila melanogaster somatic mutation and recombination test (SMART) using standard (ST) and high bioactivation (HB) crosses. The MNT used 10 mg, 20 mg or 40 mg per 100 g of body weight (bw) of extract with and without 0.2 mg per 100 g bw peritoneal cyclophosphamide. There was no genotoxicity in the negative control or extract only groups and, compared to the cyclophosphamide control, there was a significant reduction in micronucleated polychromatic erythrocytes in all the groups given extract plus cyclophosphamide. For SMART larvae were fed 5 or 10 mg mL-1 of extract for seven days with and without 0.89 mg mL-1 of urethane given on day seven. The ST and HB flies showed no significant differences in spots between the negative control and the extract only groups. The number of urethane-induced spots was reduced by the highest concentration of extract for the ST flies and by both concentrations of extract for the HB flies. The results suggest that M. velutina extract is not genotoxic but is antigenotoxic.Genetics and Molecular Biology 01/2008; 31(3). · 0.88 Impact Factor
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ABSTRACT: The aim of this study was to investigate the genetic, oxidative and cytotoxic effects of thymol (THY) in cultured human blood cells (n=5) for the first time. Human blood cells were treated with THY (0–200 mg/L) for 24 and 48 hours, and then cytotoxicity was detected by lactate dehydrogenase (LDH) release and [3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay, while DNA damage was also analyzed by micronucleus (MN) assay, sister chromatid exchanges (SCE) assay and 8-oxo-2-deoxyguanosine (8-OH-dG) level. In addition, biochemical parameters (total antioxidant capacity [TAC] and total oxidative stress [TOS]) were examined to determine oxidative effects. In our in vitro test systems, it was observed that THY had no mutagenic effects on human lymphocytes. On the other hand, THY (at 25, 50 and 75 mg/L) treatment caused statistically important (p < 0.05) increases of TAC levels and increases of TOS levels (only at 200 mg/L) on cultured human blood cells. According to the results of LDH assay, THY induced cytotoxicity on cultured human blood cells in a time- and dose-dependent manner, and THY (at concentrations above 100 mg/L) decreased cell viability. These results suggest that THY may be the therapeutic antioxidant potential in different diseases.Journal of Essential Oil Research 11/2013; · 0.82 Impact Factor