The Yalowich lab's research involves studies of anti-tumor agents and environmental toxicants that target DNA topoisomerase II alpha (topo II), an enzyme that causes DNA strand breakage necessary for chromosome separation during mitosis. Recent studies are focused on understanding the mechanisms by which the clinically effective anticancer agent etoposide (VP-16) and the environmental carcinogen, benzene, cause acute myelogenous leukemia (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 topo II inhibition. Nutritional antioxidants such as vitamin C and vitamin E homologs are under investigation as a mechanism-based chemo-prevention strategy to eliminate VP-16- and benzene-induced AML by reducing production of peroxidase-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.
In separate studies, the mechanisms and circumvention of acquired resistance to VP-16 and to a new class of topoisomerase inhibtors, the bisdioxo-piperazines are under investigations in relationship to posttranscriptional, posttranslational, and mutational alterations in topo II. | 
