dUTPase As A Prognostic Marker in Colon Cancer

dUTPase 作为结肠癌的预后标志物

• 批准号: 6620544
• 负责人: ROBERT D LADNER
• 金额: $ 13.89万
• 依托单位: UNIV OF MED/DENT NJ-SCH OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620544
• 关键词: biomarker; clinical research; colon neoplasms; drug resistance; enzyme activity; enzyme induction /repression; fluoropyrimidine; human subject; immunocytochemistry; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; oxidoreductase; p53 gene /protein; pentosyltransferase; phosphomonoesterases; polymerase chain reaction; prognosis; thymidylate synthase

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.

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指标， 抗癌剂。该途径的抑制剂，如氟嘧啶 和抗叶酸剂诱导TTP池的严重消耗， 池不平衡和通过称为“无胸腺嘧啶死亡”的过程杀死细胞。" 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， 细胞杀伤这项建议的主要目标是更好地了解 参与dUTP代谢的关键酶在调节 化疗敏感性在这项研究中，我们建议调查的预后价值 脱氧尿苷三磷酸核苷酸水解酶（dUTR）作为一种 总生存期和对基于氟尿嘧啶的化疗反应的标志物 在转移性结肠癌中。dUTP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dUTR过表达抵消了 通过限制dUTP池的扩增来抑制氟嘧啶处理。虽然 有显著的证据表明尿嘧啶-DNA代谢可能是一种 介导细胞毒性的关键因素，很少有临床研究 为了阐明人dUTR表达在调节 化疗敏感性具体目标1研究了dUTR的意义 在预测患者对基于氟尿嘧啶的反应中的表达 化疗和转移性结肠癌的总生存率。具体目标2 比较了肿瘤内dUTR表达与其他表达的预后能力， 已知的结肠直肠癌的预后标志物，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。将dUTR表达作为预后标志物的临床分析将不 仅为结肠癌的评估和治疗提供有用的工具 患者，但也将提供额外的洞察异常的作用， 在抑制胸苷酸代谢的化疗中的尿嘧啶-DNA代谢。