This application is in response to NOT-OD-09-058, """"""""NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications"""""""". The existing NIH grant RO1 CA90787 is entitled, """"""""Mechanisms and Prevention of Etoposide-Induced Leukemia"""""""". The central hypothesis is that redox cycling of the phenolic anticancer agent etoposide (VP-16) by myeloperoxidase (MPO) found in myeloid progenitors amplifies the genotoxicity and carcinogenicity of this DNA topoisomerase II (topo II)-targeted agent leading to MLL gene translocations and therapy-related acute myelogenous leukemia (t-AML). It is also posited that nutritional antioxidants such as vitamin C and vitamin E homologs will prevent VP-16-induced AML by reducing or preventing production of peroxidase-dependent redox cycling species. In the present competitive revision, we propose to study benzene-induced leukemogenesis and its prevention. These studies are beyond the scope of the original application and are predicated on the following knowledge: 1) benzene-induced AML also displays MLL gene translocations;2) benzene leukemogenesis has been linked to cytochrome P450 oxidation to phenolic derivatives;3) phenolic benzene metabolites inhibit topo II in a manner analagous to VP-16 (also a phenolic compound). Hence, the hypothesis to be tested in this competitive revision is that MPO-catalyzes oxidative reactions of phenolic benzene metabolites in myeloid progenitors to yield carcinogenic species that act via inhibition of topo II. Specifically it is proposed that oxidative damage and abasic DNA sites formed as a consequence of MPO-induced activation of benzene phenols result in loci known to poison topo II causing recombinogenic DNA strand breakage. It is further proposed that nutritional antioxidants will prevent benzene-induced AML by preventing production or scavenging of MPO-derived free radical and electrophilic metabolites. In order to test the stated hypotheses two specific aims will be pursued to: 1) establish the role of MPO and the bioreductive enzyme NAD(P)H:quinone oxidoreductase (NQO1) in phenolic benzene oxidative activation, oxidative DNA damage, and topo II poisoning in MPO-rich HL60 cells and in growth factor mobilized CD34+ progenitor cells. 2) determine the effects of nutritional antioxidants such as: 1) vitamin C;2) vitamin E homologs: 3) a combination of these antioxidants with dihydrolipoate (to recycle ascorbate) in preventing MPO-catalyzed oxidation of phenolic benzene metabolites and other downstream events linked to MLL gene associated leukemogenesis. Relevance: This competitive revision of an existing grant will investigate whether the free radical forms of benzene produced in myeloid progenitor cells are responsible for specific DNA aberrations causal for myeloid leukemia and whether nutritional antioxidants can protect cells from benzene genotoxicity and carcinogenicity.
This proposed research plan will: 1) examine the mechanism(s) by which the environmental carcinogen benzene causes acute myelogenous leukemia (AML);2) evaluate an antioxidant strategy for limiting this problem. It is proposed that free radical and other oxidized forms of phenolic benzene metabolites produced in normal myeloid progenitor cells (by action of the enzyme myeloperoxidase) are responsible for specific DNA aberrations causal for AML. A major goal will be to determine the role of nutritional antioxidant supplementation in diminishing formation and reactions of oxidized benzene metabolites, thereby reducing pathogenic DNA damaging events. Results obtained will contribute fundamental new information regarding the genesis and prevention of benzene-induced leukemia.
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