BIOCHEMICAL MODULATION WITH TRANSPORT INHIBITORS

哺乳动物细胞对核苷的摄取是复杂的，并通过 多种转运蛋白。随着关于这些属性的数据的增加 运输商越来越清楚地看到，两者之间存在着差异 底物的特异性和对抑制剂的敏感性。此外， 在转运蛋白的分布上有一些不同 可能用于化疗的肿瘤和正常组织。其中之一 最引人注目的是钠依赖的集中转运的存在 在几个正常组织中存在，但在大多数肿瘤细胞中不存在。既然那- 依赖的核苷转运体不受NBMPR或 双嘧达莫(两种平衡转运蛋白的抑制剂 大多数肿瘤细胞)，有可能调节抗代谢 这些抑制剂的活性。该项目的目标1将进一步定义 核苷转运活动存在于关键的正常组织中，如 如肠道和骨髓，以及核苷可能发生的变化 肠道细胞分化过程中的运输。第二个目标是 这个项目将检验这样一个假设，即高度选择性的治疗可以 使用De-nevo抑制剂为部分(但不是全部)肿瘤开发 联合转运抑制剂阻断嘧啶生物合成 核苷回收。这种治疗方法被预测是有效的。 针对主要对NBMPR敏感的核苷转运的肿瘤，但 对于具有显著NBMPR不敏感转运水平的肿瘤则不适用。 小鼠L1210白血病，它含有四种已知核苷中的三种 L1210的转运子和亚系缺乏一个或多个 运输车将被用作样板。这将使我们能够评估 每种转运体在肿瘤抗共同免疫反应中的作用 背景关于可能影响药物活性的其他因素。 第三个目标将检验选择性治疗可以是 为对NBMPR不敏感的核苷转运的肿瘤开发使用 细胞毒性核苷类似物与转运抑制剂联合作用 阻断正常组织对类似物的摄取。这将再次完成 利用L1210肿瘤模型确定各转运体的作用 关系到治疗的成败。最后一个目标将应用这些 免疫系统中作为异种移植生长的人类肿瘤的治疗方法 被剥夺的小鼠和培养中的AS细胞系。体外/体内模型 将再次允许我们在生化水平上检查原因 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.