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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Cancer Therapeutics Program Project Review Committee (CTR)
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Mayer, D; Natsumeda, Y; Ikegami, T et al. (1990) Expression of key enzymes of purine and pyrimidine metabolism in a hepatocyte-derived cell line at different phases of the growth cycle. J Cancer Res Clin Oncol 116:251-8
Grunicke, H H; Yamada, Y; Natsumeda, Y et al. (1989) Histone acetyltransferase activity in rat hepatomas. J Cancer Res Clin Oncol 115:435-8
Pillwein, K; Reardon, M A; Jayaram, H N et al. (1988) Insulin regulatory effects on purine- and pyrimidine metabolism in alloxan diabetic rat liver. Padiatr Padol 23:135-44
Snell, K; Natsumeda, Y; Eble, J N et al. (1988) Enzymic imbalance in serine metabolism in human colon carcinoma and rat sarcoma. Br J Cancer 57:87-90
Natsumeda, Y; Ikegami, T; Murayama, K et al. (1988) De novo guanylate synthesis in the commitment to replication in hepatoma 3924A cells. Cancer Res 48:507-11
Prajda, N; Natsumeda, Y; Ikegami, T et al. (1988) Enzymic programs of rat bone marrow and the impact of acivicin and tiazofurin. Biochem Pharmacol 37:875-80
Hashimoto, Y; Shiotani, T; Eble, J N et al. (1988) Increased thymidylate synthase (EC activity in normal and neoplastic proliferation. Cancer Biochem Biophys 10:1-10
Weber, G; Jayaram, H N; Lapis, E et al. (1988) Enzyme-pattern-targeted chemotherapy with tiazofurin and allopurinol in human leukemia. Adv Enzyme Regul 27:405-33
Yamada, Y; Natsumeda, Y; Weber, G (1988) Action of the active metabolites of tiazofurin and ribavirin on purified IMP dehydrogenase. Biochemistry 27:2193-6
Pillwein, K; Jayaram, H N; Weber, G (1987) Effect of ischemia on nucleosides and bases in rat liver and hepatoma 3924A. Cancer Res 47:3092-6

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