Induction of somatic mutation and recombination by four inhibitors of eukaryotic topoisomerases assayed in the wing spot test of Drosophila melanogaster.
Four inhibitors of eukaryotic topoisomerases were investigated for genotoxic effects in the wing spot test of Drosophila melanogaster. As a somatic mutation and recombination test (SMART) this assay assesses mitotic recombination and mutational events of various kinds. We studied camptothecin as a topoisomerase I inhibitor, as well as ellipticine as an intercalating inhibitor and teniposide and etoposide as two non-intercalating inhibitors of topoisomerase II. Wing spots were induced in flies trans-heterozygous for the recessive wing cell markers multiple wing hairs (mwh) and flare (flr3) as well as in flies heterozygous for mwh and the multiply inverted TM3 balancer chromosome. All four compounds proved significantly genotoxic in this test. The spot induction frequencies formally standardized to the millimolar unit of exposure dose decreased in the order camptothecin > teniposide > ellipticine greater, similar etoposide in the mwh/flr3 inversion-free genotype. In the mwh/TM3 genotype, in which mitotic crossing over is suppressed because of the inversion-heterozygosity, the observed spot frequencies were considerably reduced, but to different extents. In this genotype, spot induction by ellipticine was not statistically significant, and it was determined that >99% of the spots are due to mitotic recombination in mwh/flr3 flies. For the other compounds, spot induction in the inversion-heterozygous genotype was significant. The relative contribution of recombination to total spot induction in the inversion-free genotype was 88% for camptothecin. It was significantly lower for the two epipodophyllotoxins teniposide (71%) and etoposide (59%). Only suggestions can be proffered at present as to how these proportions could be related to the primary damage produced by the respective compounds on the chromosomes.
Frei
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Institute of Toxicology, Swiss Federal Institute of Technology (ETH) and University of Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland.
Würgler
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D000818:Animals; D002166:Camptothecin / Q000494:pharmacology; D004331:Drosophila melanogaster / Q000235:genetics; D004611:Ellipticines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods*; D009154:Mutation; D011995:Recombination, Genetic / Q000187:drug effects*; D013713:Teniposide / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors
D004611:Ellipticines; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; C034192:ellipticine; D005047:Etoposide; D013713:Teniposide; D002166:Camptothecin