Potentiation of antimetabolite action by uridylate trapping.

Uridylate-trapping analogs of D-galactose or D-glucose divert the uridylate moiety of UDPglucose and/or UTP to UDP-sugar analogs that accumulate while the pools of UTP and of related pyrimidine nucleotides are depleted. The uridylate-trapping action of sugar analogs is determined by the enzyme pattern of the target tissue. D-Galactose analogs are preferentially metabolized by hepatoma cells and hepatocytes. TA3-mammary tumor cells are susceptible to the action of D-glucosamine and other D-glucose analogs. A high rate of de novo pyrimidine synthesis and/or an active salvage of extracellular uridine compensate for the uridylate-trapping action of sugar analogs and prevent depletion of UTP pools. Accordingly, synergistic actions are induced by combining sugar analogs, such as D-galactosamine or D-glucosamine, with inhibitors of de novo pyrimidine synthesis, such as lapachol or 6-azauridine. Uridylate-trapping by D-galactosamine, acting on hepatocytes, shifts the balance between uridine consumption and uridine release by the liver and results in a fall of uridine and cytidine concentrations in blood plasma (20). Cultured hepatocytes produce uridine and cytidine. Combination of 5-fluorouridine with sugar analogs results in the formation of fluorinated UDP-sugar analogs in hepatoma cells or in mammary tumor cells. Formation of FUDP-sugar analogs transiently removes intracellular FUTP, but FUDP can be released subsequently in glycosyltransferase reactions (22). Pretreatment of hepatoma cells or of TA3-mammary tumor cells with an uridylate-trapping sugar analog in combination with an inhibitor of de novo pyrimidine synthesis enhances the uptake of 5-fluorouridine, its incorporation into RNA, and its growth inhibitory effect. The chemotherapeutic action of 5-fluorouridine in rats and mice, carrying the AS-30D and the TA3 ascites tumor, respectively, is significantly improved by pretreatment with an amino sugar together with 6-azauridine.