Mutagenesis, Vol. 17, No. 2, 141-147,
March 2002
© 2002 UK Environmental Mutagen Society/Oxford University Press
Comparison of camptothecin derivatives presently in clinical trials: genotoxic potency and mitotic recombination
Departamento de Ciências Fisiológicas, Universidade Federal de Goiás, CP 131, 74001-970 Goiânia, GO, Brasil, 1 Laboratório de Mutagênese, Departamento de Genética, Universidade Federal do Rio Grande do Sul, CP 15053, 91501-970 Porto Alegre, RS, Brasil and 2 Institute of Animal Sciences, Section Physiology and Animal Husbandry, Swiss Federal Institute of Technology (ETH) Zürich, CH-8603 Schwerzenbach, Switzerland
The genotoxicity of camptothecin (CPT) and its clinical antineoplastic analogues irinotecan (CPT-11) and topotecan (TPT) were evaluated using the wing somatic mutation and recombination test (SMART) in Drosophila melanogaster. These compounds stabilize and trap the topoisomerase I–DNA complex, preventing the religation step of the breakage/rejoining reaction mediated by the enzyme. The standard version of the wing SMART was used to evaluate the three compounds and to compare the wing spots induced in marker-heterozygous and balancer-heterozygous flies. The results demonstrate that all compounds tested have a significant genotoxic effect in both genotypes analysed. At the same time, a comparison of the clone induction frequencies in marker-heterozygous and balancerheterozygous flies shows that mitotic recombination is the prevalent mechanism through which the three compounds induce all categories of wing spots (78–93% recombination). TPT was the most genotoxic compound, probably because substitutions of amino groups for the 9-carbon of the CPT A ring leads to compounds with greater in vivo activity. CPT and CPT-11 induced, respectively, about 7 and 28 times fewer mutant clones per millimolar exposure unit than TPT.
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