MODULATION OF 5-FLUOROURACIL ACTIVITY IN COLON CARCINOMA

5-氟尿嘧啶是目前最活跃的药物可用于 治疗结直肠癌，但它仍然只有7-15%的反应， 率 5-氟尿嘧啶的活性可显著增加， 将其与亚叶酸结合，其作用是最大化5-氟尿嘧啶 抑制胸苷酸合成酶。 然而，仍然有可能， 一些肿瘤细胞能够通过挽救 外源性胸苷 已经进行了临床试验， 双嘧达莫是否可以增强5-氟尿嘧啶或5-氟尿嘧啶的活性 氟尿嘧啶/甲酰四氢叶酸通过阻断胸苷补救水平 运输，但结果令人失望。 由于胸苷 在哺乳动物细胞中，转运是复杂的， 对抑制剂具有不同敏感性的转运蛋白， 核苷转运的差异导致了高水平的 潘生丁在这些患者中有效性的患者间差异 养生法 这是本项目的基本假设， 平衡核苷转运蛋白如双嘧达莫和NBMPR可 增强5-氟尿嘧啶对部分但非全部结肠的活性 肿瘤;并且组合的功效将与 肿瘤细胞的核苷转运特性。 该项目将 通过四个具体目标来检验这一假设：（1）界定 一组人结肠癌细胞核苷转运特性 并将细胞的核苷转运表型与 转运抑制剂调节5-羟色胺活性的能力 氟尿嘧啶在体外对这些肿瘤细胞的作用;（2）比较 体内转运效应的体外研究结果 胸苷补救和氟嘧啶核苷酸抑制剂 在作为异种移植物生长的人结肠肿瘤中的积累 （3）比较转运抑制剂对小鼠脑组织的影响。 5-氟尿嘧啶/亚叶酸的体内抗肿瘤活性 不同的核苷转运特性;和（4）开发 评估肿瘤细胞中核苷转运蛋白类型的方法 从新鲜的结肠肿瘤样品中分离，并使用这些方法 确定新鲜组织中核苷转运蛋白表型的异质性， 肿瘤的 目标1至3中的研究旨在定义 “核苷转运表型”，其易受用 5-氟尿嘧啶/亚叶酸联合核苷转运 目标4应该允许我们估计这些抑制剂的发生率， 在新鲜的人结肠肿瘤标本中的表型。

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.