ROLE AND FUNCTIONS OF PYRIMIDINES IN CANCER THERAPY

说明：（申请人的摘要）尿苷已被证明在细胞内起关键作用。 在调节氟嘧啶的细胞毒性作用中的作用， 和肿瘤组织。尿苷在血浆和组织中的浓度是 受尿苷磷酸化酶（UPase）活性和 细胞内转运机制。申请人已利用抑制 尿苷磷酸化酶通过苄酰基尿苷（BAU）升高尿苷 在血浆和正常组织中的浓度，以减少 5-氟尿嘧啶（5-FU）。在过去的几年里，他发现了一系列 正常细胞和肿瘤细胞在控制和调节 尿苷水平可用于实现更有选择性的细胞毒性， 肿瘤，更好地保护作为主要靶点的正常组织， 氟嘧啶毒性，从而提高治疗指数 5-氟尿嘧啶。本申请集中于UPase在调节细胞凋亡中的作用。 正常与肿瘤组织中尿苷的细胞内水平， 表征这种酶及其调节，以及如何存在的 人类乳腺肿瘤中的一种新的磷酸解活性可能有助于 增强正常组织的选择性拯救，同时维持 氟嘧啶在人乳腺肿瘤中的细胞毒性作用。拟议 研究还将解决一些关于生理学的关键问题， 尿苷和尿苷磷酸化酶的功能：1）为什么尿苷的浓度 血浆中的尿苷与其他核苷不同， 不同的物种，2）为什么肿瘤表型的诱导结果 直接或间接提高尿苷磷酸化酶活性，和 3)为什么乳腺肿瘤组织具有BAU不敏感的磷酸化活性 不是胸苷磷酸化酶为了实现这些目标，研究 将集中在两个主要项目的进展：隔离和表征 负责BAU不敏感磷酸解活性的蛋白质 存在于人乳腺肿瘤中，以及评估UPase在乳腺癌中的作用。 尿苷稳态及其在5-FU抗肿瘤治疗中的作用具体 通过以下方式实现UPase遗传信息的改变：a）靶向 破坏UPase基因以使UPase等位基因无效，以及相反地，B）UPase 基因转移以提高组织中的UPase表达和活性。

DESCRIPTION: (Applicant's Abstract) Uridine has been shown to play a crucial role in modulating the cytotoxic effects of fluoropyrimidines in both normal and tumor tissues. The concentration of uridine in plasma and in tissues is tightly regulated by the activity of uridine phosphorylase (UPase) and by intracellular transport mechanisms. The applicant has utilized inhibition of uridine phosphorylase by benzylacyclouridine (BAU) to elevate uridine concentration in plasma and normal tissues to reduce the toxic effect of 5-fluorouracil (5-FU). During the past few years he has uncovered a series of differences between normal and tumor cells in the control and regulation of uridine levels that can be exploited to achieve more selective cytotoxicity in tumors, better protection of normal tissues that are primary targets of fluoropyrimidine toxicity, and thereby to improve the therapeutic index of 5-fluorouracil. The application focuses on the role of UPase in regulating the intracellular level of uridine in normal versus tumor tissue, on the characterization of this enzyme and its regulation, and on how the presence of a new phosphorolytic activity in human breast tumors can contribute to enhancing the selective rescue of normal tissues while maintaining the cytotoxic effect of fluoropyrimidines in human breast tumors. The proposed studies will also address some critical questions regarding the physiological function of uridine and uridine phosphorylase: 1) why the concentration of uridine in plasma, unlike other nucleosides, is so tightly regulated throughout different species, 2) why the induction of the neoplastic phenotype results directly or indirectly in the elevation of uridine phosphorylase activity, and 3) why breast tumor tissues have a BAU-insensitive, phosphorolytic activity that is not thymidine phosphorylase. To achieve these objectives the research will center on two main projects in progress: isolation and characterization of the protein(s) responsible for the BAU-insensitive phosphorolytic activity present in human breast tumors, and the evaluation of the role of UPase in uridine homeostasis and its effect on 5-FU antitumor therapy. Specific alterations of UPase genetic information will be achieved by: a) targeted disruption of UPase gene to nullify the UPase allele, and conversely, b) UPase gene transfer to elevate the UPase expression and activity in tissues.