Despite recent breathtaking advances in cancer genetics and treatment, anticancer drug resistance remains a formidable problem and challenge to oncologists and researchers alike. The long-term goal of this project has been the dissection of mechanisms of antitumor multidrug resistance. It is now clear that anticancer drug resistance at the cellular level, even to a single agent, is a multifactorial phenomenon; multiple genetic changes can occur in a tumor cell selected for resistance to any particular cytotoxic agent. Not known, however, is whether these alterations are a cause or consequence of selection for resistance. Thus the hypothesis to be tested in this application is that anticancer drug treatment perturbs many cellular components that can provide a selective advantage for tumor cell survival and contribute to the anticancer drug resistance phenotype. Building on work done in the prior funding period, the applicant proposes a focused application to test this hypothesis, using different classes of topoisomerase inhibitors and his unique panel of tumor cell lines, selected for resistance to them as a paradigm for cytotoxic drug action and resistance. These novel cell lines will provide the platform for the proposed genetic and biochemical studies. To test the hypothesis, the following specific aims are proposed: 1) characterize the functions of topoisomerase (topo) II-alpha and beta and topo I in drug sensitive and resistant cells through the use of molecularly-engineered enzymes and accessory proteins; 2) describe the regulation of expression of topo II alpha and beta in drug sensitive and resistant cells through the studies of transcription factors, chromatin accessibility, and promoter methylation; 3) identify elements in the cytotoxic signaling pathways induced by complex-stabilizing and catalytic topoisomerase inhibitors through selective studies of cDNA array technology; and 4) utilize knowledge of these resistance mechanisms to develop novel approaches to circumvent resistance to these inhibitors, including gene therapy.
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