The objective of this program is further improvement in the treatment and management of cancer patients. This will be sought through the development of new agents and regimens and means for circumvention of acquired resistance in patients under treatment for various neoplastic disorders. To accomplish this goal, a series of coordinated, multidisciplinary investigational activities are proposed. These extend our advances in the following areas. New classical folate analogues will be evaluated as antitumor agents. The design of new homologues of methotrexate and 10- ethyl-10-deazaminopterin (10EDAM) incorporates structural features found to be important for the highly promising clinical activity of 10EDAM in nonsmall-cell lung cancer patients. Studies are also proposed on newly designed analogues of folic acid and tetrahydrofolate that are inhibitors of combinations of antifolates with DNA interacting agents. The synthesis and evaluation are proposed of novel classes of intercalating agents with alkylating capability that are among those already developed in this program that potently inhibit either topoisomerase I or II. Aspects of the mechanism of action and acquired resistance of these new folate analogues and new topoisomerase inhibitors are also sought. A major effort is also proposed on the problem of multidrug resistance (MDR). These studies will focus on """"""""early events"""""""" in the initiation of MDR at the level of P- glycoprotein and the relationship between these events and neoplastic potential and cellular differentiation. MDR variants will be studied with the view to characterizing two prevalent P-glycoproteins, P170 and P180 and a new candidate, MS-1, putatively associated with MDR, that appears to be a differentiation marker during maturation of murine intestinal epithelial cells. These studies will examine aspects of P-glycoprotein gene expression and transcriptional regulation as well as biochemical mechanisms at both laboratory and clinical levels. The latter will address a number of questions related to P-glycoprotein-mediated MDR and its circumvention in the treatment and pathogenesis of leukemia and of a few selected solid tumor using molecular probes, immuno-histochemistry and flow cytometry. Facilities and resources provided in two Core Laboratories will allow rapid biological evaluation and clinical exploitation of promising new findings.
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