Elucidating the targets of antileukemic agents: Molecular mechanisms of mercaptopurine action

Mercaptopurine and thioguanine are anticancer and immunosuppresive agents t hat exert their primary cytotoxic effects via incorporation of deoxythiogua nosine into DNA. Elucidation of molecular mechanisms underlying the sensiti vity/resistance to thiopurine drugs is essential to further improving the t herapy for leukemia. Inherited deficiency in thiopurine S-methyltransferase activity determines idiosyncratic reactions to thiopurines. Isolation and cloning of mutant alleles from humans with thiopurine S-methyltransferase d eficiency has helped to develop PCR-based genotyping assays for this disord er. Incorporation of deoxythioguanosine into DNA substantially alters DNA-p rotein interactions at several steps of DNA replication. Importantly, it pr events RNA hydrolysis by RNase H in the DNA-RNA heteroduplex, and decreases the thermal stability of the DNA duplexes.