The cellular pharmacology of the antineoplastic nucleoside, cyclopentenyl cytosine, (CPEC), and of the antiretroviral nucleoside, dideoxyguanosine, (ddG), has been examined in cultured Molt-4 lymphoblasts. CPEC is converted to nine metabolites in these cells: cyclopentenyl uridine (CPEU), CPEU-MP, CPEU-DP and CPEU-TP; CPEC-MP, CPEC-DP and CPEC-TP, along with two phosphodiesterase-sensitive nucleotides provisionally identified as CPEC-DP-choline and CPEC-DP-ethanolamine. CPEC-TP accumulates rapidly in these cells, ultimately reaching levels 100-200 times those of parent drug in the medium; such levels of CPEC-TP can be measured by HPLC without recourse to radiolabel, a feature of value for the forthcoming clinical trials with CPEC. Molt-4 cells incubated with 5(mu)M tritiated ddG, (97% of the label being in the sugar moiety) generate the active metabolite, ddGTP in concentrations just adequate to inhibit retroviral reverse transcriptase. The accumulation of ddGTP from ddG can be enhanced modestly by co-incubation with 2'-deoxyadenosine but is markedly stimulated by ribavirin, an antiviral agent in its own right. Tiazofurin and mycophenolic acid produce comparable stimulations, a feature which makes it likely that inhibition of IMP dehydrogenase, of which all these are potent inhibitors, is the common cause of their stimulatory effects on ddG anabolism.
