Ortho-catechols related to the naturally-occurring catecholamines levodopa and dopamine have been shown to be potent antitumor agents in a broad spectrum of experimental tumors, including B16 melanoma, C1300 neuroblastoma, and L1210 and P388 lymphocytic leukemias. Previous synthetic work has produced two analogs, 3,4-dihydroxybenzylamine and N-acetyl 3,4-dihydroxybenzylamine, which have significantly improved antitumor activity and are capable of producing long-term survivors in the experimental leukemias. We now propose to conduct a synthetic program generating new compounds based on the biologic data developed during the initial portion of this grant. Toxicologic and pharmacologic analysis of drug metabolism, pharmacokinetics, and host toxicity should provide the necessary foundation for the rational design of a third generation of agents with enhanced antitumor activity. Toxicologic data will also begin to address the questions that must be answered prior to the consideration of these agents as potentially applicable to the cancer problem in man. Biochemical studies have focused upon the identification of the site of action of these agents with DNA polymerase and ribonucleotide reductase as the principal sites of action. Effects upon each of the other potential enzyme targets--dihydrofolate reductase, thymidylate synthetase, and dNMP kinase--will be examined using purified enzyme preparations as well as permeabilized cells in wild type and drug-resistant mutants. Based upon mechanism of action, the intriguing question of the basis of antitumor cell selectivity, especially in the non-melanoma cells, will be addressed using short-term cultures of tumor cells and bone marrow cells derived from L1210-bearing mice. Hopefully, it will enable us to examine quantitatively the basis of antitumor selectivity and possibly demonstrate a significant metabolic difference between tumor cells and normal cells that may be of fundamental significance. We intend that this multifaceted approach will continued to generate important biologic data which can be immediately applied to the synthesis of improved agents, and concurrently, accrue the necessary data to determine which of these agents appears to be justified for continued development towards ultimate clinical trial in man.
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