Comparison of camptothecin derivatives presently in clinical trials: genotoxic potency and mitotic recombination.
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 balancer-heterozygous 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.
Cunha
Kênya Silva
KS
Departamento de Ciências Fisiológicas, Universidade Federal de Goiás, CP 131, 74001-970 Goiânia, GO, Brasil.
Reguly
Maria Luíza
ML
Graf
Ulrich
U
Rodrigues de Andrade
Heloisa Helena
HH
D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives / Q000633:toxicity*; D002986:Clinical Trials as Topic; D004249:DNA Damage / Q000187:drug effects*; D004331:Drosophila melanogaster / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D000077146:Irinotecan; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods*; D009154:Mutation; D011995:Recombination, Genetic / Q000187:drug effects*; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000633:toxicity; D014921:Wings, Animal / Q000002:abnormalities / Q000187:drug effects
D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D019772:Topotecan; D002166:Camptothecin