A comprehensive and integrated program is planned to test the molecular correlation concept in human cancer cells and the design of enzyme pattern-targeted chemotherapy. The long-term objective is to provide novel observations and creative ideas for an integrated, rational approach toward disease-oriented, enzyme- and biochemical-pattern-targeted chemotherapy.
The specific aims are to elucidate linking of enzymic and metabolic features of malignant cells with transformation and progression in rat model systems and in human colon adenocarcinoma, hepatocellular carcinoma and myelogenous and lymphocytic leukemias. The following 4 related projects comprise the coordinated program. 1. Elucidation of the characteristic pattern of the biochemical strategy of cancer cells in purine, pyrimidine and serine metabolism. 2. Elucidation of the enzymic and biochemical determinants of selective toxicity and resistance to anti-metabolites (tiazofurin, selenazofurin, and acivicin) in tumors and normal tissue. 3. Investigation of chemotherapy with anti-metabolites and combination therapy with transport inhibitors and alkylating agents. 4. Study of biochemical impact of drugs in human myelogenous and lymphocytic leukemic cells and in human colon adenocarcinoma cells as a predicting system and as an indicator of sensitivity and resistance to the chemotherapeutic agents. The methods and procedures required for acccomplishing the research objectives are operative in this Laboratory. Other techniques are readily adapted from the literature. Understanding the stringency of linkage of enzymic and metabolic features of malignant cells with transformation and progression and the selective advantages these alterations confer to cancer cells should reveal strategic enzymic and biochemical alterations that should be sensitive targets in the design of selective chemotherapy in animals and in human neoplasia.
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