The long-term objective is to utilize our understanding of important aspects of the biochemical strategy of cancer cells for the rational design of anti-cancer drug treatment focussing on enzyme-pattern-targeted chemotherapy. I. The molecular basis of neoplasia will be elucidated by investigating strategic aspects of the altered pattern of the activities of key enzymes, metabolic pathways and nucleotide pools and the linking of the imbalance with transformation and the degrees in the expression of malignancy (progression) in models and in human neoplasms to provide a rational basis for the design of anti-cancer chemotherapy. 1. Regulations of pyrimidine and DNA metabolism will be clarified with focus on control of activities of pathways and key enzymes of de novo (carbamoyl-phosphate synthetase II, CTP synthetase, CDP reductase) and salvage (uridine-cytidine, deoxycytidine and thymidine kinases) synthesis and of the metabolism of uridylates, cytidylates and thymidine. Nutritional and hormonal regulation will be clarified. 2. Thymidine kinase, carbamoyl-phosphate synthetase II, CTP, FGAM and GMP synthetases will be purified. 3. Regulation of PRPP content and of the activities of enzymes that produce and utilize PRPP will be elucidated. 4. Regulation of tissue ornithine content and the activities of the utilzing enzymes (ornithine decarboxylase, carbamoyltransferase and transaminase) will be determined. II. The second avenue of attack utilizes our elucidation of the biochemical strategy of cancer cells for rational design of drug treatment focusing on enzyme-pattern-targeted-chemotherapy. The impact of the drugs on the target enzymic activities and the pools of nucleotides will be correlated with cytotoxicity and chemotherapeutic action. 1. The metabolic action and chemotherapeutic use of the anti-glutamine drug, acivicin, will be determined as a single agent and in combination with the transport inhibitor, dipyridamole, and the RNA polymerase inhibitor, actinomycin. 2. The action of the anti-IMP dehydrogenase drugs, tiazofurin and selenazofurin, the anti-GMP synthetase drug, acivicin, and the inhibitor of CDP reductase, VF122, will be elucidated. 3. The alkylating agent, lycurim, will be studied in combination with anti-metabolites (pyrazofurin, tiazofurin). 4. Galactosamine treatment will be tested with acivicin or VF122 and dipyridamole. Rescue will be tested with orotate which is transported into normal but not into cancer cells. The role of galactokinase will be clarified as a possible predictor of UTP trapping in galactosamine treatment in tumors. 5. The mechanism of resistance to acivicin, tiazofurin and VF122 will be elucidated and overcome.
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