L-DOPA ANALOGS AS NEW ANTITUMOR AGENTS

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Antitumor agents containing the 1,2-dihydroxybenzene moiety represent a new structural class of antitumor agent with activity against a broad spectrum of experimental tumors including L1210, P388 leukemia and B-16 melanoma. Mechanistic studies have suggested that the drugs interfere selectively with DNA synthesis primarily through effects upon ribonucleotide reductase, DNA polymerase and thymidylate synthase. Emphasis will be placed upon the study of the mechanism of action of these drugs and the relationship of redox potential to antitumor activity. Specifically, the effect of the drugs upon 3 additional redox sensitive DNA synthetic enzymes, DHFR, thioredoxin reductase and glutaredoxin reductase will be evaluated using isolated enzyme preparations. The effect of dihydroxybenzene compounds on ribonucleotide reductase and DHFR will be examined using in situ assays. The general concept of the influence of reducing agents upon DNA synthesis in eukaryotic cells will be addressed with specific emphasis upon the effect on the level of endogenous reductants. A correlation between the antiproliferative effects and depletion of levels NADPH and other cellular reductants will be investigated. Detailed studies of the effects of catechols upon nucleotide pools will be performed in order to gain additional information as to the causes and biochemical consequences of the inhibition of DNA synthesis. Hopefully, this work will lead to a better understanding of the mechanism of suppression of DNA synthesis by catechols and the remarkable antitumor selectivity observed. In particular, the studies of the effects on the intracellular redox state might provide insight into metabolic difference between normal and malignant cells with respect to the manner in which they interact with these antiproliferative reducing agents.