The goal of this proposal is to gain an understanding of the biochemical and molecular basis for the cytotoxic action of three clinically effective nucleoside analogues. The application focuses upon the cellular pharmacology and molecular action of arabinosylcytosine (ara-C), arabinsoyladenine (ara-A) and arabinosyl 2-fluoroadenine (F-ara-A). Correlations will be sought between the cellular concentrations of the active arabinosyl triphosphates and the corresponding deoxynucleoside triphosphate for evidence of a competitive relationship in the inhibition of DNA synthesis. The effects of arabinosyl nucleotides on the deoxynucleotide levels in synchronous cell populations will be evaluated to test the hypothesis of """"""""self-potentiation"""""""" as applied to ara-A and F-ara-A. The quantitative relationship between cytotoxicity and incorporation of arabinosyl nucleotides into DNA will be studied and compared to determine whether incorporation of a certain number of arabinosyl residues will elicit a defined cytotoxic effect. The mutagenic action of arabinosyl nucelosides will be compared and the genetic bases for observed mutations will be sought. The incorporation of F-ara-A into RNA will be characterized and the consequences to transcription and translation of a specific gene will be studied. Finally, the ability of arabinosyl nucleosides to inhibit the repair of drug-induced DNA damage will be correlated with their cellular metabolism and the consequences of this inhibition for cytotoxicity will be considered.
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