The purpose of this 5-year renewal proposal is to strengthen and expand the research programs on Metabolic Regulation in Neoplasia and Chemotherapy presently carried out in the Laboratory for Experimental Oncology of Indiana University School of Medicine, Indianapolis, IN. The individual research projects include investigations on (1) regulation of metabolism and chemotherapy of neoplasia (2) clinicopathologic and chemotherapeutic studies of human renal adenocarcinomas and human colonic adenocarcinomas (3) enzyme pattern-directed antipurine chemotherapy of tumors (4) regulation of purine biosynthesis, salvage and degradation; antipurine drugs (5) metabolic imbalance and antipyrimidine chemotherapy in animals and tissue culture (6) metabolic programs of cancer cells and chemotherapy with alkylating agents and antimetabolites (7) regulation of key enzymes of IMP synthesis and catabolism; action of antiglutamine agents (8) regulation of pyrimidine and glutamine metabolism and chemotherapy. The program is targeted to a central theme, to elucidate the regulation of enzymes and metabolic pathways linked with normal and neoplastic proliferation to achieve a rational design of chemotherapy; to this central theme each project relates and contributes. A deeper insight into regulation of gene expression should lead to a rational design of enzyme-pattern-directed selective chemotherapy in animals and in human. Our approach is planned to accelerate the acquisition of knowledge and conceptual progress more effectively than would a simple aggregate of research projects operating without such a thematic integration. The proposed renewal would enable us to achieve the objectives also by supporting one Central Core Facility for animal colony, tumor transplantation and maintenance to be shared by investigators involved in this program and by providing salaries for the young scientists. The main approach is the integration of modern experimental chemotherapy, oncology, enzymology, metabolic regulation and biochemical pharmacology to achieve selective chemotherapy of experimental and human neoplasia.
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