BIOCHEMICAL MODULATION WITH TRANSPORT INHIBITORS

哺乳动物细胞对核苷的摄取是复杂的，并由 多种转运蛋白。 随着数据的增加， 越来越明显的是， 底物特异性和对抑制剂的敏感性。 此外，委员会认为， 在一些国家和地区之间， 肿瘤和正常组织，可能在化疗中被利用。 之一 最引人注目的是存在Na+依赖的集中转运 在一些正常组织中，但在大多数肿瘤细胞中没有。 由于Na+- 依赖性核苷转运蛋白不受NBMPR抑制， 潘生丁（在体内发现的两种平衡转运蛋白的抑制剂） 大多数肿瘤细胞），存在抗代谢物调节的潜力 这些抑制剂的活性。 该项目的目标1将进一步确定 存在于关键正常组织中的核苷转运活性 如肠和骨髓，以及核苷 肠细胞分化过程中的运输。 的第二个目的 该项目将测试高度选择性治疗可以 开发了一些，但不是所有的肿瘤，使用从头抑制剂， 嘧啶生物合成与转运抑制剂组合以阻断 核苷补救 这种治疗方法预计是有效的 针对主要具有NBMPR敏感性核苷转运的肿瘤，但是 不针对具有显著水平的NBMPR不敏感转运的肿瘤。 小鼠L1210白血病，其中有三个已知的核苷 L1210的一种或多种转运蛋白和亚系缺陷， 运输机将被用作模型。 这将使我们能够评估 每种转运蛋白在肿瘤对常见的 其他可能影响药物活性的因素。 第三个目标是检验选择性治疗可以 开发用于具有NBMPR不敏感核苷转运的肿瘤， 细胞毒性核苷类似物与转运抑制剂的组合， 阻断正常组织对类似物的摄取。 这将再次完成 使用L1210肿瘤模型来确定每种转运蛋白的作用 治疗的成败 最后一个目标将适用于这些 在免疫系统中作为异种移植物生长的人类肿瘤的治疗方法 剥夺小鼠和作为培养物中的细胞系。 体外/体内模型 将再次使我们能够在生化水平上检查 治疗策略的成败。

The uptake of nucleosides by mammalian cells is complex and mediated by multiple transport proteins. As data increases on the properties of these transporters it is becoming increasingly clear that there are differences in their substrate specificity and sensitivity to inhibitors. Furthermore, there are differences in the distribution of the transporters between some tumors and normal tissues that might be exploited in chemotherapy. One of the most striking is the presence of Na+-dependent, concentrative transport in several normal tissues, but not in most tumor cells. Since Na+- dependent nucleoside transporters are not inhibited by NBMPR or dipyridamole (inhibitors of the two equilibrative transporters found in most tumor cells), there is potential for the modulation of antimetabolite activity with these inhibitors. Aim 1 of this project will further define the nucleoside transport activities present in critical normal tissues such as intestine and bone marrow, and changes that may occur in nucleoside transport during differentiation of intestinal cells. The second aim of this project will test the hypothesis that highly selective therapy can be developed for some, but not all, tumors using inhibitors of de novo pyrimidine biosynthesis in combination with transport inhibitors to block nucleoside salvage. This therapeutic approach is predicted to be effective against tumors with predominantly NBMPR-sensitive nucleoside transport, but not against tumors with significant levels of NBMPR-insensitive transport. The mouse L1210 leukemia, which has three of the four known nucleoside transporters, and sublines of L1210 that are deficient in one or more of the transporters will be used as a model. This will allow us to evaluate the role of each of the transporters in tumor response against a common background with respect to other factors that may affect drug activity. The third aim will test the hypothesis that selective therapy can be developed for tumors with NBMPR-insensitive nucleoside transport using a cytotoxic nucleoside analog in combination with a transport inhibitor to block uptake of the analog by normal tissues. This will again be done using L1210 tumor model to determine the role of each of the transporters in the success or failure of therapy. The last aim will apply these therapeutic approaches to human tumors that grow as xenografts in immune deprived mice and as cell lines in culture. The in vitro/in vivo model will again permit us to examine at the biochemical level reasons for success or failure of the therapeutic strategy.