Evaluation of genotoxic potential of vincristine from multiple parameters

Abstract

The genotoxic potential of vincristine is assessed by in vivo and in vitro cytogenetic assays on two test systems using multiple parameters. In in vivo experiments it was administered intraperitoneally to Swiss albino mice at doses computed on a surface area basis to lie within the therapeutic range. The parameters employed include screening of chromosome mutational activity in bone marrow and meiotic cells for periods covering one spermatogenetic cycle, in vivo SCE analysis and sperm head abnormality assay. In vitro studies included conventional scoring for chromosome mutations from human leucocyte cultures following administration of the drug at doses within the therapeutic range on the basis of blood volume. Strict controls were employed in both test systems. The data were treated by appropriate statistical tests to evaluate their validity. The results of in vivo experiments on somatic as well as meiotic test systems reveal a lack of clastogenic action of the compound. Both sexes respond in an identical fashion regarding this activity. The SCE analysis supports the in vivo nonclastogenic action of vincristine. Total univalents significantly seen with the highest dose after 1 and 2 weeks must be considered as being important as they can lead to aneuploidy. Evidence is adduced from sperm head abnormality assay that the drug induces point mutations. The results from in vitro test system indicate a positive chromosome mutational property. This is substantiated by results of in vitro SCE analysis. A comparison of data from in vivo and in vitro test systems suggests that a metabolic conversion of the compound in the former might render it innocuous for expressing the chromosome mutational activity. They also point out that vincristine evokes a differential clastogenic response in the two test systems despite bringing about an anaphase arrest commonly in both by acting on cytokinesis.