Regulation of ribonucleotide reductase activity and its possible exploitation in chemotherapy

Abstract

Although 2′-deoxyadenosine inhibits the growth of many organisms it is not inhibitory for Lactobacillus leichmannii. This is consistent with the presence of a powerful trans-N-deoxyribosylase in this organism, as well as the absence of any inhibitory effects of dATP on its ribonucleotide reductase. Specific activating effects of deoxyribonucleoside triphosphates on the reduction of ribonucleotides catalyzed by the L. leichmannii reductase did not act to equalize the production of pyrimidine and purine deoxyribonucleotides when GTP, ATP, CTP and UTP were reduced simultaneously in vitro. Under all conditions investigated dGTP and dATP were formed at a much greater rate than dCTP and dUTP. Deoxytubercidin has an ED 50 for CCRF-CEM cells considerably lower than that for deoxyadenosine and only slightly higher than that for deoxyadenosine in the presence of an inhibitor of adenosine deaminase. This observation suggests that other analogs of deoxyadenosine may efficiently inhibit mammalian cell proliferation via conversion to dATP analogs which inhibit mammalian ribonucleotide reductase.