Modulation of O6-alkylating agent induced clastogenicity by enhanced DNA repair capacity of bone marrow cells

Abstract The murine bone marrow micronucleus assay has been used to examine (1) the potentiation of fotemustine and streptozotocin induced-clastogenicity by the O 6 -alkylguanine-DNA alkyltransferase (ATase) inactivator O 6 -benzylguanine ( O 6 -beG) and (2) the level of protection afforded against this potentiation by retrovirus-mediated expression of an O 6 -beG-resistant mutant of human ATase (hATPA/GA) in mouse bone marrow. Both fotemustine and streptozotocin induced significantly higher levels of micronucleated polychromatic erythrocytes ( p O 6 -beG ( p O 6 -beG-resistant hATPA/GA as a result of retroviral gene transfer, the frequency of micronucleus formation following exposure of mice to otherwise clastogenic doses of fotemustine or streptozotocin, in the presence of O 6 -beG, was highly significantly reduced ( p O 6 -chloroethyl- and O 6 -methylguanine as clastogenic lesions in vivo and establish ATase as a major protective mechanism operating to reduce the frequency of such damage. The potentiation of drug induced clastogenicity by O 6 -beG suggests that the clinical use of this inactivator in combination with O 6 -alkylating agents, could substantially increase the risk of therapy related malignancy. Nevertheless the use of hATPA/GA as a protective mechanism via gene therapy may overcome this risk.