ROLE AND FUNCTION OF PYRIMIDINES IN CANCER THERAPY

描述：(申请人摘要)治疗方法的改进 氟嘧啶类药物对乳腺癌的疗效是这项研究的主要目标。 申请。5-FU是联合用药中最活跃的药物之一 转移性乳腺癌和胃肠道肿瘤的化疗。为了增加 FU治疗指数有限，新发现的肿瘤之间的差异 而处理尿苷的正常组织将被开发。 具体地说，依赖于钠离子的尿苷转运体的差异， 它可能在人类肿瘤中缺乏，以及尿苷磷酸化酶，用于 其中BAU不敏感的活性可以在肿瘤中选择性地发现，将 被追捕。这两个行动都会导致较低水平的 肿瘤细胞与正常细胞中的尿苷；因为尿苷已被证明 在适当的条件下，防止FU的细胞毒性 对正常组织的选择性保护可以在没有 影响FU的抗肿瘤作用。如果发生这种情况，剂量 然后可以安全地升级FU。 评价正常人和正常人尿苷转运体的差异 对于肿瘤组织，申请者将测量 兔肾钠离子依赖性转运蛋白的基因探针研究 尿苷转运蛋白和另一种核苷转运蛋白的基因探针 从老鼠的肠道上皮中分离出来；他还将尝试克隆和 人肾组织中人类基因的全长cDNA鉴定 图书馆。他将产生针对转运蛋白的抗体 探查外科标本以寻找这种集中机制的丢失 尿苷。为了进一步深化他的观察，多达50%的 某些人类肿瘤的尿苷磷酸化酶活性不敏感 BAU，一种有效的尿苷磷酸化酶抑制剂，申请者将 纯化非BAU敏感形式的尿苷磷酸化酶；动力学 表征两种酶催化活性的差异 正常和肿瘤人体组织标本；完成克隆 用于酶的cDNAs和制备蛋白质的抗体；评估 在人类肿瘤和正常组织中表达；并启动结构 通过确定BAU的结合域来确定酶的性质 利用光亲和或共价标记探针。在具体目标3中， 申请者将继续他的临床前和临床评估 BAU在人乳腺癌异种移植模型和I-II期试验中的应用 确定具有以下特点的BAU方案是否可以提高FU的MTD 已证实可引起血浆尿苷水平的靶向变化。

DESCRIPTION: (Applicant's Abstract) Improvement of the therapeutic efficacy of fluoropyrimidines in breast cancer is the main goal of this application. 5-FU is one of the most active drugs used in combination chemotherapy of metastatic breast and GI carcinoma. To increase the limited therapeutic index of FU, newly found differences between tumor and normal tissue in the disposition of uridine will be exploited. Specifically, differences in the Na+-dependent uridine transporter, which may be deficient in human tumors, and uridine phosphorylase, for which a BAU-insensitive activity may be selectively found in tumors, will be pursued. Both of these actions would tend to lead to lower levels of uridine in tumor vs normal cells; since uridine has been shown to protect against FU cytotoxicity, under the appropriate conditions a selective protection of normal tissue could be achieved without compromising the antitumor effect of FU. Were this to occur, the dose of FU could then be safely escalated. To evaluate differences in the uridine transporter between normal and neoplastic tissues, the applicant will measure expression of the transporter using a cDNA probe for the rabbit kidney Na+-dependent uridine transporter and another cDNA probe for a nucleoside transporter from rat intestinal epithelium; he will also attempt to clone and characterize the cDNA for the human gene from a human kidney cDNA library. He will generate antibodies against the transporter protein to probe surgical specimens for loss of this concentrative mechanism for uridine. To further pursue his observation that as much as 50% of uridine phosphorylase activity in selected human tumors is not sensitive to BAU, a potent inhibitor of uridine phosphorylase, the applicant will purify the non-BAU sensitive form of uridine phosphorylase; kinetically characterize differences in the catalytic activity of the enzymes from normal and neoplastic human tissue specimens; complete the cloning of the cDNA for the enzyme and prepare antibodies to the proteins; assess expression in human tumors and normal tissues; and initiate structural characterization of the enzyme by defining the binding domain for BAU utilizing photoaffinity or covalent labeling probes. In specific aim 3, the applicant will continue his preclinical and clinical evaluation of BAU in a human breast cancer xenograft model and in a Phase I-II trial to determine if the MTD of FU can be raised by a BAU regimen that has been demonstrated to cause target changes in plasma uridine levels.