ROLE AND FUNCTION OF PYRIMIDINES IN CANCER THERAPY

描述：（申请人的摘要）治疗性的改进 氟嘧啶在乳腺癌中的疗效是本研究的主要目标， 应用程序. 5-FU是联合应用最活跃的药物之一 转移性乳腺癌和胃肠道癌的化疗。增加 FU的治疗指数有限，新发现的肿瘤之间的差异 并利用尿苷分布的正常组织。 具体而言，Na+依赖性尿苷转运蛋白， 它可能在人类肿瘤中缺乏，尿苷磷酸化酶， 其BAU不敏感活性可选择性地在肿瘤中发现， 被追求。这两种行动往往会导致低水平的 肿瘤细胞与正常细胞中的尿苷;由于尿苷已被证明 在适当的条件下， 可以实现正常组织的选择性保护， 损害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。 为了评价正常人和正常人尿苷转运蛋白的差异， 在肿瘤组织中，申请人将测量 用cDNA探针研究兔肾Na+依赖性转运蛋白 尿苷转运蛋白和另一种核苷转运蛋白的cDNA探针 他还将尝试克隆， 表征来自人肾cDNA的人基因的cDNA 图书馆他将产生针对转运蛋白的抗体， 探针手术标本的损失，这种集中机制， 尿苷。为了进一步研究他的观察， 尿苷磷酸化酶活性在选定的人类肿瘤中不敏感 BAU是尿苷磷酸化酶的有效抑制剂，申请人将 纯化尿苷磷酸化酶的非BAU敏感形式;动力学 表征酶的催化活性与 正常和肿瘤性人体组织标本;完成 cDNA的酶和制备抗体的蛋白质;评估 在人类肿瘤和正常组织中表达;并启动结构 通过定义BAU的结合结构域来表征酶 利用光亲和性或共价标记探针。在具体目标3中， 申请人将继续进行临床前和临床评价， 人乳腺癌异种移植模型和I-II期试验中的BAU 确定是否可以通过BAU方案提高FU的MTD， 已被证明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.