Inhibitors of DNA topoisomerase (topo) I and II are some of the newer agents used in the treatment of human malignancies. The cytotoxic effect of these is dependent on the nuclear activity of the target enzyme. The more topoisomerase in the nucleus the more effective the inhibitor. Recent preclinical data suggest that there is an optimal sequence of administration of anti-neoplastic agents (i.e., DNA-damaging agent->topo I inhibitor->topo II inhibitor) determined by levels of topo I and II. This hypothesis will be examined in vivo. Several mechanisms of drug resistance to topo inhibitors have been defined in vitro. A hypothesis to be examine din this project of the MOPP application is that alterations in the amount, activity, or location or location of topo I and II are involved in drug resistance in multiple myeloma, NHL, AML and ovarian cancer. Recent studies in the laboratory of the applicant suggest that changes in trafficking of topo IIalpha, which are growth phase- or adhesion- dependent, may also determine drug sensitivity Further studies in vitro to examine the shuttling of topoisomerases at a molecular level, as well as experiments to define mechanisms of resistance to sequential alkylator- >topo I inhibitor or topo I inhibitor-> II inhibitor exposure, may suggest other mechanisms that are operational in vivo. These hypotheses and mechanisms will be addressed through the following specific aims. 1. To determine if a specific sequence of anti-tumor agents has a biochemical justification in vivo in the high-dose chemotherapy of both multiple myeloma and NHL, as well as in the induction chemotherapy of AML. 2. To define the roles of an altered subcellular distribution of attenuation of the expression/activity of topo I or II in the drug resistance of selected hematologic malignancies and ovarian cancer. 3. To compare the mechanisms of drug resistance of selected hematologic malignancies and ovarian cancer. 3. To compare the mechanisms of drug resistance in human multiple myeloma cell lines isolated in the presence of a single drug versus a specific sequence of drugs. 4. To examine the modulation of topo IIalpha trafficking in models of drug resistance that are dependent on either growth stage or fibronectin adhesion. By examining both the molecular basis of anti-tumor drug sequencing and the role of alterations of topo I and II in the drug resistance both the molecular basis of anti- tumor drug sequencing and the role of alterations of topo I and II in the drug resistance of myeloma, NHL and ovarian cancer, these studies may suggest more effective approaches to the treatment of these diseases.
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