Abstract
The roles of the converting enzymes cytidine deaminase (CD) and deoxycytidylate deaminase (dCMPD) in the metabolism and cytotoxicity of a variety of pyrimidine nucleoside analogs was investigated in vitro.In vitro studies suggest that 5-fluorodeoxycytidine (FdC) and 5-trifluoromethyldeoxycytidine (F(,3)methyl dC) require deamination as a step in their metabolism to a cytotoxic metabolite. Marked reduction in the cytotoxicity of these analogs could be achieved through the use of the deaminase inhibitors, tetrahydrouridine (H(,4)U) and deoxytetrahydrouridine (dH(,4)U). Cells devoid of deaminase activity at both levels were highly resistant to these analogs.The inhibition of deamination at both the nucleoside and nucleotide level with dH(,4)U increased the toxicity of 5-fluorodeoxyuridine (FdU). Cytosine arabinoside (ara-C) activity was reduced when deamination at both levels was inhibited with dH(,4)U. These results are best explained by the perturbations in endogenous pool sizes produced by dH(,4)U.F(,3)methyl dC showed marked tumor inhibitory activity against the murine tumors Adenocarcinoma-755 and Lewis Lung Carcinoma (LLC) in vivo. In comparative studies with trifluorothymidine F(,3)methyl dC resulted in equivalent or better antitumor activity with less morbidity and mortality.FdC showed high activity vs. LLC in vivo and the activity could be increased with H(,4)U. The increased activity with H(,4)U suggests increased phosphorylation of FdC as such and lends credence to the approach of exploiting elevations in dCMP activity associated with human malignant neoplasms since they would theoretically be most sensitive to the increased levels of FdCMP.