MODULATION OF 5-FLUOROURACIL ACTIVITY IN COLON CARCINOMA

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5-Fluorouracil is currently the most active drug available for the treatment of colorectal carcinoma, but it still has only a 7-15% response rate. The activity of 5-fluorouracil can be increased significantly by combining it with leucovorin, which acts to maximize 5-fluorouracil inhibition of thymidylate synthase. It is still likely, however, that some tumor cells are able to escape 5-fluorouracil toxicity by salvaging exogenous thymidine. Clinical trials have been undertaken to test whether dipyridamole can potentiate the activity of 5-fluorouracil or 5- fluorouracil/leucovorin by blocking thymidine salvage at the level of transport, but the results have been disappointing. Since thymidine transport is complex in mammalian cells and can be mediated by multiple transporters with differing sensitivities to inhibitors, it is likely that differences in nucleoside transport contribute to a high degree of interpatient variability in the effectiveness of dipyridamole in these regimens. It is the basic hypothesis of this project that inhibitors of equilibrative nucleoside transporters such as dipyridamole and NBMPR can potentiate the activity of 5-fluorouracil against some, but not all colon tumors; and that the efficacy of the combination will be related to the nucleoside transport properties of the tumor cells. This project will test that hypothesis through four specific aims: (1) to define the nucleoside transport properties of a panel of human colon tumor cell lines and compare the nucleoside transport phenotype of the cells to the ability of transport inhibitors to modulate the activity of 5- fluorouracil against these tumor cells in vitro; (2) to compare the results of the in vitro studies to the in vivo effects of transport inhibitors on thymidine salvage and fluoropyrimidine nucleotide accumulation in human colon tumors growing as xenografts in immune deprived mice; (3) to compare the effects of transport inhibitors on the antitumor activity of 5-fluorouracil/leucovorin in vivo against tumors that differ in their nucleoside transport properties; and (4) to develop methods to assess the types of nucleoside transporters in tumor cells isolated from fresh colon tumor samples and use those methods to determine the heterogeneity of nucleoside transporter phenotypes in fresh tumors. The studies in Aims 1 through 3 are designed to define "nucleoside transport phenotypes" that are susceptible to therapy with 5-fluorouracil/leucovorin in combination with a nucleoside transport inhibitor, and Aim 4 should allow us to estimate the incidence of those phenotypes in fresh human colon tumor specimens.