MODULATION OF 5-FLUOROURACIL ACTIVITY IN COLON CARCINOMA

5-氟尿嘧啶是目前治疗卵巢癌最活跃的药物 治疗结直肠癌，但它的反应仍然只有7%-15% 费率。5-氟尿嘧啶的活性可通过以下方式显著提高 将其与亚叶酸钙联合使用，亚叶酸钙可使5-氟尿嘧啶最大化 胸苷合成酶的抑制。然而，仍然有可能， 一些肿瘤细胞能够通过挽救逃脱5-氟尿嘧啶的毒性 外源性胸腺嘧啶核苷已经进行了临床试验以测试 双嘧达莫是否能增强5-氟尿嘧啶或5-氟尿嘧啶的活性 氟尿嘧啶/亚叶酸钙阻断胸腺嘧啶核苷挽救 交通，但结果一直令人失望。由于胸苷 哺乳动物细胞的转运是复杂的，可以由多个 对抑制剂敏感性不同的转运蛋白，很可能 核苷转运的差异在很大程度上导致了 潘生丁在这些患者中的疗效的患者间差异 养生法。这是该项目的基本假设，即抑制剂 平衡的核苷转运体，如潘生丁和NBMPR可以 增强5-氟尿嘧啶对某些但不是全部结肠的活性 肿瘤；联合用药的疗效将与 肿瘤细胞的核苷转运特性。这个项目将 通过四个具体目标来检验这一假设：(1)定义 一组人结肠肿瘤细胞的核苷转运特性 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 氟尿嘧啶对这些肿瘤细胞的体外抗肿瘤作用；(2)比较 体内转运效应的体外研究结果 胸腺嘧啶核苷回收和氟嘧啶核苷酸的抑制剂 免疫系统中异种移植生长的人结肠肿瘤中的蓄积 剥夺小鼠；(3)比较转运抑制剂对小鼠的影响 5-氟尿嘧啶/亚叶酸钙体内抗肿瘤活性 核苷转运性质不同的；和(4)发展 评价肿瘤细胞核苷转运蛋白类型的方法 从新鲜的结肠癌样本中分离出来，并使用这些方法 鲜肉中核苷转运蛋白表型异质性的测定 肿瘤。目标1至3中的研究旨在定义 对药物敏感的“核苷转运表型” 5-氟尿嘧啶/亚叶酸钙联合核苷转运 抑制剂，目标4应该使我们能够估计这些 新鲜人类结肠癌标本的表型。

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.