dUTPase As A Prognostic Marker in Colon Cancer

描述（由申请人提供）： 40 多年来，胸苷酸 代谢已成为广泛应用的重要生化靶点 抗癌剂。该途径的抑制剂，例如氟嘧啶 和抗叶酸剂会导致 TTP 库严重耗尽，从而导致核苷酸 通过称为“无胸腺嘧啶死亡”的过程来调节细胞池失衡和细胞杀伤。 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 损伤的重要介质 细胞杀伤。该提案的主要目标是更好地理解 参与 dUTP 代谢的关键酶在调节中的作用 化学敏感性。在本研究中，我们建议调查预后价值 脱氧尿苷三磷酸核苷酸水解酶（dUTPase）作为 总体生存率和对氟嘧啶化疗反应的标志物 在转移性结肠癌中。 dUTPase 催化 dUTP 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 过度表达会抵消 dUTPase 的细胞毒性作用 通过限制 dUTP 库的扩展进行氟嘧啶治疗。虽然 有重要证据表明尿嘧啶-DNA 代谢可能是 介导细胞毒性的关键因素，但临床研究较少 旨在阐明人 dUTPase 表达在调节中的作用 化学敏感性。具体目标 1 研究 dUTPase 的意义 预测患者对氟嘧啶类药物反应的表达 化疗和转移性结肠癌的总生存期。具体目标2 比较了瘤内 dUTPase 表达与其他疾病的预后能力 已知的结直肠癌预后标志物，包括胸苷酸合酶 (TS)、胸苷磷酸化酶(TP)、二氢嘧啶脱氢酶(DPD)和 第 53 页。 dUTPase 表达作为预后标志物的临床分析不会 只为结肠癌的评估和治疗提供有用的工具 患者，但也将提供对异常的作用的更多见解 抑制胸苷酸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.