dUTPase As A Prognostic Marker in Colon Cancer

描述(申请人提供)：40多年来，胸腺嘧啶 代谢已成为一项重要的生化指标，得到了广泛的应用 抗癌药物。这一途径的抑制剂，如氟嘧啶类 而抗叶酸会导致TTP池的严重耗尽，导致核苷酸 通过一种被称为“百里香无氧死亡”的过程，细胞池失衡和细胞死亡。 对这一过程的潜在机制的研究表明， 尿嘧啶-DNA代谢异常可能是DNA损伤和 细胞杀戮。这项建议的广泛目标是更好地理解 参与dUTP代谢的关键酶在调节中的作用 对化学药物敏感。在这项研究中，我们建议调查预后的价值。 脱氧尿苷三磷酸核苷酸水解酶(DUTPase)作为一种 以氟嘧啶为基础的化疗总存活率和疗效的标志物 转移性结肠癌。DUTP酶催化dUTP的水解形成 Dump和PPI，从而从DNA生物合成途径中消除dUTP。我们 假设dUTPase的过度表达抵消了细胞毒作用 通过限制dUTP池的扩张进行氟嘧啶治疗。虽然 有重要证据表明尿嘧啶-DNA代谢可能是一种 介导细胞毒性的关键因素，临床研究很少 目的是阐明人dUTPase表达在调节 对化学药物敏感。特定目的1研究dUTPase的意义 基因表达在预测氟嘧啶类药物疗效中的作用 化疗与转移性结肠癌的总存活率。具体目标2 比较瘤内dUTPase表达与其他肿瘤预后的关系 已知的结直肠癌预后标记物包括胸苷合成酶 (TS)、胸苷磷酸化酶(TP)、二氢嘧啶脱氢酶(DPD)和 P53。DUTPase表达作为预后标志物的临床分析不会 仅为结肠癌的评估和治疗提供了有用的工具 患者，但也将提供更多的洞察异常的作用 抑制胸苷代谢的化疗中的尿嘧啶-DNA代谢。

DESCRIPTION (provided by applicant): For more than 40 years, thymidylate metabolism has been an important biochemical target for widely utilized anti-cancer agents. Inhibitors of this pathway such as the fluoropyrimidines and antifolates induce a severe depletion of TTP pools resulting in nucleotide pool imbalance and cell killing through a process termed "thymineless death." Investigation of the underlying mechanisms of this process suggest that aberrant uracil-DNA metabolism may be an important mediator of DNA damage and cell killing. The broad objectives of this proposal are to better understand the role of key enzymes involved in dUTP metabolism in modulating chemosensitivity. In this study, we propose to investigate the prognostic value of the enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase) as a marker for overall survival and response to fluoropyrimidine-based chemotherapy in metastatic colon cancer. dUTPase catalyzes the hydrolysis of dUTP to form dUMP and PPi, thereby eliminating dUTP from the DNA biosynthetic pathway. We hypothesize that dUTPase overexpression counters the cytotoxic effect of fluoropyrimidine treatment by limiting the expansion of dUTP pools. Although there is significant evidence suggesting that uracil-DNA metabolism may be a critical factor in mediating cytotoxicity, there have been few clinical studies performed to clarify the role of human dUTPase expression in modulating chemosensitivity. Specific aim 1 investigates the significance of dUTPase expression in predicting patient response to fluoropyrimidine-based chemotherapy and overall survival in metastatic colon cancer. Specific aim 2 compares the prognostic ability of intratumoral dUTPase expression with other known prognostic markers of colorectal cancer including, thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) and p53. Clinical analysis of dUTPase expression as a prognostic marker will not only provide a useful tool for the evaluation and treatment of colon cancer patients, but will also provide additional insight into the role of aberrant uracil-DNA metabolism in chemotherapies that inhibit thymidylate metabolism.