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Use of tiazofurin to enhance the metabolism and cytotoxic activities of analogues of guanine, guanosine, and deoxyguanosine.

An effective modulator of cellular guanine nucleotide pools, 2-beta-D-ribofuranosylthiazole-4-carboxamide (tiazofurin) was tested for its ability to affect utilization of certain guanine, guanosine, and deoxyguanosine analogues by Chinese hamster ovary cells and hypoxanthine guanine phosphoribosyltransferase (HGPRTase)-deficient variants. The nucleoside analogues investigated were chosen for their potential to be metabolized to the nucleotide level by pathways other than those requiring the action of HGPRTase. Exposure of tiazofurin-treated (500 microM for 3 h) cells to 3-deazaguanosine (200 microM for 3 h) resulted in enhanced 3-deazaGTP formation and an increase (5-10-fold) in the ratio 3-deazaGTP/GTP. Tiazofurin treatment also stimulated [3H]deoxyguanosine utilization (8-fold) by HGPRTase-deficient cells, and accordingly, greatly increased the cytotoxicity of 2'-deoxy-3-deazaguanosine and arabinosylguanine. This study emphasizes the potential usefulness of tiazofurin in sequential combination with appropriate analogues of guanosine and deoxyguanosine in a clinical setting and as a tool in studying the metabolism of these agents.