MODULATION OF BLEOMYCIN-INDUCED MITOTIC RECOMBINATION IN YEAST BY THEAMINOTHIOLS CYSTEAMINE AND WR-1065

The cancer chemotherapy drug bleomycin (BLM) is a potent inducer of ge netic damage in a wide variety of assays. The radioprotectors cysteami ne (CSM) and WR-1065 have been shown in previous studies to potentiate the induction of micronuclei and chromosome aberrations by BLM in G(0 ) human lymphocytes. By contrast, WR-1065 is reported to reduce the in duction of hprt mutations by BLM in Chinese hamster cells. To elucidat e the basis for these interactions, we examined the effects of CSM and WR-1065 on the induction of mitotic gene conversion by BLM in the yea st Saccharomyces cerevisiae. Treatment with BLM causes a dose-dependen t increase in the frequency of mitotic gene conversion and gene mutati ons. Unlike its potentiation of BLM in G(0) lymphocytes, WR-1065 prote cted against the recombinagenicity of BLM in yeast. CSM was also stron gly antirecombinagenic under some conditions, but the nature of the in teraction depended strongly on the treatment conditions. Under hypoxic conditions, cysteamine protected against BLM, but under oxygen-rich c onditions CSM potentiated the genetic activity of BLM. The protective effect of aminothiols against BLM may be ascribed to the depletion of oxygen required for the activation of BLM and the processing of BLM-in duced damage. Aminothiols may potentiate the effect of BLM by acting a s an electron source for the activation of BLM and/or by causing confo rmational alterations that make DNA more accessible to BLM. The result s indicate that aminothiols have a strong modulating influence on the genotoxicity of BLM in yeast as they do in other genetic assays. Moreo ver, the modulation differs markedly depending on physiological condit ions. Thus, yeast assays help to explain why aminothiols have been obs erved to potentiate BLM in some genetic systems and to protect against it in others.