INDUCTION OF SOMATIC MUTATION AND RECOMBINATION BY 4 INHIBITORS OF EUKARYOTIC TOPOISOMERASES ASSAYED IN THE WING SPOT-TEST OF DROSOPHILA-MELANOGASTER

Four inhibitors of eukaryotic topoisomerases were investigated for gen otoxic effects in the wing spot test of Drosophila melanogaster. As a somatic mutation and recombination test (SMART) this assay assesses mi totic recombination and mutational events of various kinds, We studied camptothecin as a topoisomerase I inhibitor, as well as ellipticine a s an intercalating inhibitor and teniposide and etoposide as two non-i ntercalating inhibitors of topoisomerase II, Wing spots were induced i n flies trans-heterozygous for the recessive wing cell markers multipl e wing hairs (mwh) and flare (flr(3)) as well as in flies heterozygous for mwh and the multiply inverted TM3 balancer chromosome, All four c ompounds proved significantly genotoxic in this test, The spot inducti on frequencies formally standardized to the millimolar unit of exposur e dose decreased in the order camptothecin > teniposide > ellipticine greater than or similar to etoposide in the mwh/flr(3) 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 th is genotype, spot induction by ellipticine was not statistically signi ficant, and it was determined that >99% of the spots are due to mitoti c recombination in mwh/flr(3) flies, For the other compounds, spot ind uction in the inversion-heterozygous genotype was significant, The rel ative contribution of recombination to total spot induction in the inv ersion-free genotype was 88% for camptothecin, It was significantly lo wer for the two epipodophyllotoxins teniposide (71%) and etoposide (59 %). Only suggestions can be proffered at present as to how these propo rtions could be related to the primary damage produced by the respecti ve compounds on the chromosomes.