Research DescriptionDr. Yalowich's recent studies are focused on understanding the mechanisms by which the clinically effective anticancer agent etoposide (VP-16), a phenolic compound, and the environmental carcinogen, benzene, can cause therapy-related acute myelogenous leukemia (t-AML). The central testable hypothesis is that redox cycling of VP-16 and phenolic benzene metabolites initiated by myeloperoxidase (MPO) in bone marrow precursors amplifies the genotoxicity and carcinogenicity of these compounds via enhanced inhibition/poisoning of DNA topoisomerase II. Nutritional antioxidants such as vitamin C and vitamin E homologs are under investigation as a mechanism-based chemoprevention strategy to eliminate VP-16- and benzene-induced AML by reducing production of MPO-dependent free radical and electrophilic metabolites. The long-term goal of these studies is to increase the clinical efficacy of VP-16 in the treatment of cancer, and to prevent benzene leukemogenesis.