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ROLE OF DUTPASE EXPRESSION IN CANCER CHEMOTHERAPY

DuTPase 表达在癌症化疗中的作用

基本信息

批准号：
6626718
负责人：
ROBERT D LADNER
金额：
$ 26.53万
依托单位：
UNIV OF MED/DENT NJ-SCH OSTEOPATHIC MED
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-01-09 至 2004-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6626718
关键词：
acid anhydride hydrolase cell line clinical research colon neoplasms combination chemotherapy enzyme activity enzyme induction /repression floxuridine fluorouracil human subject human therapy evaluation isozymes leucovorin metastasis mitochondria neoplasm /cancer chemotherapy uridine triphosphate western blottings

项目摘要

For more than forty 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, long-term objectives of this proposal are: 1) to elucidate the role of aberrant dUTP metabolism as a molecular mechanism of cell killing induced by chemotherapeutic agents that target thymidylate biosynthesis and; 2) to better understand the role of key enzymes involved in dUTP metabolism in modulating chemosensitivity. In this study, the applicants propose a mechanistic analysis of thymineless death using human colon cancer cell lines that over express the enzyme deoxyuridine triphosphate nucleotide hydrolase (dUTPase). dUTPase catalyzes the hydrolysis of dUTP to form dUMP and PPi, thereby eliminating dUTP from the DNA biosynthetic pathway. The applicants hypothesize that dUTPase over-expression counters the cytotoxic effect of FUdR 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 no biochemical studies performed to clarify the role of human dUTPase isoform expression in modulating chemosensitivity. The proposed studies are designed to correlate key mechanistic hallmarks of uracil-DNA mediated cytotoxicity with cell death induced by fluorodeoxyuridine. Specific Aim 1 investigates the role of dUTPase isoform over-expression as a mechanism of resistance to FUdR-induced cytotoxicity. Specific Aim 2 investigates the correlation between biochemical endpoints of aberrant uracil-DNA metabolism and chemosensitivity to FUdR. Specific Aim 3 investigates the significance of dUTPase isoform expression in predicting patient response to fluoropyrimidine-based chemotherapy and overall survival in metastatic colon cancer. A better understanding of the role of aberrant uracil-DNA metabolism in mediating thymineless death should not only enhance our knowledge of the molecular mechanism of drug action of these important chemotherapeutics, but also provide insight into novel and improved treatment strategies.

40多年来，胸苷代谢一直是一种广泛使用的抗癌药物的重要生化指标。抑制剂这一途径，如氟嘧啶和抗叶酸，会导致严重的 TTP池耗尽导致核苷酸池失衡和细胞杀伤通过一个被称为“百里香的死亡”的过程。对潜在原因的调查这一过程的机制提示，尿嘧啶-DNA代谢异常可能是是DNA损伤和细胞死亡的重要媒介。广泛的、长期的这项建议的目的是：1)阐明异常dUTP的作用新陈代谢是化疗诱导细胞杀伤的分子机制靶向胸苷生物合成的试剂和；2)更好地了解参与dUTP代谢的关键酶在调节化疗敏感性中的作用。在这项研究中，申请者提出了一种无胸腺体的机械分析用过度表达该酶的人结肠癌细胞系致死脱氧尿苷三磷酸核苷酸水解酶(DUTPase)。DUTP酶催化 DUTP的水解形成DUMP和PPI，从而从DNA中消除dUTP 生物合成途径。申请者假设dUTPase过度表达通过限制细胞的扩张来对抗FUDR治疗的细胞毒作用 DUTP池。尽管有重要证据表明尿嘧啶脱氧核糖核酸新陈代谢可能是介导细胞毒性的关键因素，已经有没有进行任何生化研究来阐明人dUTPase亚型的作用在调节化疗敏感性中的表达。拟议的研究旨在尿嘧啶脱氧核糖核酸介导的细胞毒性的关键机制特征与氟代脱氧尿苷诱导的细胞死亡。具体目标1调查角色 DUTPase亚型过表达作为FUDR诱导抗性机制的研究细胞毒性。特定目标2研究生化指标之间的相关性尿嘧啶脱氧核糖核酸代谢异常的终点与FUDR的化疗敏感性。特异靶3研究dUTPase异构体在肺癌中的表达意义预测患者对以氟嘧啶为基础的化疗的反应转移性结肠癌的存活率。更好地理解在介导胸腺嘧啶脱氢酶死亡中尿嘧啶-DNA代谢异常不仅应该加强我们对这些化合物药物作用的分子机制的认识重要的化疗药物，但也提供了对新的和改进的洞察治疗策略。