Novel opportunities for thymidylate metabolism as a therapeutic target.
Novel opportunities for thymidylate metabolism as a therapeutic target.
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DOI：
10.1158/1535-7163.mct-08-0280
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发表时间：
2008-09
影响因子：
5.7
通讯作者：
Ladner RD
中科院分区：
文献类型：
--
作者：
Wilson PM;Fazzone W;LaBonte MJ;Deng J;Neamati N;Ladner RD
40多年来，氟嘧啶5-氟尿嘧啶（5-FU）一直是治疗结直肠癌（CRC）的治疗方案中的中心药物，经常与DNA损伤剂奥沙利铂和伊立替康联合使用，以提高缓解率并改善总生存期。然而，许多患者将从治疗中获得很少或没有益处，这突出了识别新的治疗靶点以提高当前基于5-FU的化疗策略的疗效的需要。脱氧尿苷三磷酸核苷酸水解酶（Deoxyuridine triphosphate nucleotidohydrolase，dUTH）催化dUTP水解为dUMP和PPi，为胸苷酸合成酶（thymidylate synthase，TS）和DNA合成及修复提供底物。虽然dUTP是DNA合成中的正常中间体，但它的积累和错误掺入DNA作为尿嘧啶是致命的。重要的是，尿嘧啶错误掺入代表了TS靶向类化疗药物（包括5-FU）诱导的细胞毒性的重要机制。越来越多的证据表明，dUTR是一个重要的介导的TS靶向药物的反应。在这份手稿中，我们提出了进一步的证据表明，dUTR的表达升高可以保护乳腺癌细胞免受细胞内尿嘧啶池的扩增，转化为5-FU治疗后的生长抑制减少。因此，我们报告了计算机药物开发技术的实施，以识别和开发dUTR的小分子抑制剂。由于5-FU和口服5-FU前药卡培他滨仍然是治疗各种恶性肿瘤的中心药物，因此小分子抑制剂对dUTR的临床效用代表了改善这些主要化疗药物临床疗效的可行策略。
For over 40 years, the fluoropyrimidine 5-fluorouracil (5-FU) has remained the central agent in therapeutic regimens employed in the treatment of colorectal cancer (CRC) and is frequently combined with the DNA-damaging agent's oxaliplatin and irinotecan increasing response rates and improving overall survival. However, many patients will derive little or no benefit from treatment, highlighting the need to identify novel therapeutic targets to improve the efficacy of current 5-FU-based chemotherapeutic strategies. Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) catalyzes the hydrolysis of dUTP to dUMP and PPi providing substrate for thymidylate synthase (TS) and DNA synthesis and repair. Although dUTP is a normal intermediate in DNA synthesis, its accumulation and misincorporation into DNA as uracil is lethal. Importantly, uracil misincorporation represents an important mechanism of cytotoxicity induced by the TS-targeted class of chemotherapeutic agents including 5-FU. A growing body of evidence suggests that dUTPase is an important mediator of response to TS-targeted agents. In this manuscript we present further evidence demonstrating that elevated expression of dUTPase can protect breast cancer cells from the expansion of the intracellular uracil pool, translating to reduced growth inhibition following treatment with 5-FU. We therefore report the implementation of in silico drug development techniques to identify and develop small molecule inhibitors of dUTPase. As 5-FU and the oral 5-FU pro-drug capecitabine remain central agents in the treatment of a variety of malignancies, the clinical utility of a small molecule inhibitor to dUTPase represents a viable strategy to improve the clinical efficacy of these mainstay chemotherapeutic agents.