Drug resistance poses a major barrier to the cure of neoplastic diseases. The long-term goal of this project has been the dissection of mechanisms of multidrug resistance (MDR). The proposed studies will focus on MDR associated with both altered expression of DNA topoisomerase II (at-MDR) and overexpression of P-glycoprotein (Pgp-MDR), as well as the mechanisms by which drugs mediate (i.e., """"""""signal"""""""") cytotoxic events. New data suggest that the cytotoxic effects of many anticancer drugs are mediated through interference with the tightly regulated cell cycle machinery, often leading to induction of programmed cell death (PCD). One hypothesis to be tested is that MDR involves alterations in cell cycle-and PCD-related proteins, and that altered drug """"""""target"""""""" proteins attenuate the cytotoxic signal transduction pathways required for full expression of PCD pathways. Different types of inhibitors of DNA topoisomerase II (topo II), including the DNA-protein complex-stabilizing drugs (e.g., etoposide) and the catalytic inhibitors (e.g., merbarone), have different cytotoxic actions in wild-type (wt) and at-MDR cells that appear to be related to either DNA damage or to inhibition of topo II function, but little is known about the mechanism(s) by which they kill tumor cells. A second hypothesis to be tested is that catalytic inhibitors of topo II activate PCD by a different route than that of complex-stabilizing inhibitors of the enzyme. Finally, modulators of Pgp-MDR can increase mdr1 and Pgp expression, but virtually nothing is known about the signaling mechanisms involved in this effect. Thus, the last hypothesis to be tested is that the induction of mdr1 by inhibition of Pgp function may interrupt a feedback signal(s) that involves transcription factors and/or novel functions of p53. To test these hypotheses, the following Specific Aims are proposed: (1) define the mechanism of at-MDR, through studies of cytotoxic signal transduction; (2) determine the mechanism of cytotoxicity of catalytic vs. complex-stabilizing topo II inhibitors in drug-sensitive and at-MDR cells; and (3) identify signalling mechanisms by which Pgp-MDR modulators induce mdr1 expression.
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