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adavosertib

肿瘤

关键词肿瘤 药物 AZD1775

词汇介绍

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解析

Adavosertib 

释    义   n. 酪氨酸激酶WEE1的小分子抑制剂,一种药物

例    句   Adavosertib in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue.

Adavosertib联合吉西他滨和放射治疗的耐受性良好,其剂量可使替代组织产生靶向作用。

概述

Wee1 激酶是参与细胞周期 G /M 检查点和DNA损伤修复过程的关键激酶。超过50%的肿瘤存p53基因缺失或突变,导致细胞周期 G1/S 检查点的缺陷,使得肿瘤细胞DNA的复制及损伤修复过程更依赖于G2/M检查点。抑制Wee1激酶活性后,肿瘤细胞的DNA损伤不能及时修复便进入M期,造成基因组不稳定性和染色体缺失,引发有丝分裂灾难,导致肿瘤细胞凋亡。adavosertib是阿斯利康公司研发的小分子选择性Wee1激酶抑制剂,通过选择性抑制Wee1激酶,阻滞p53基因缺陷型肿瘤在G2/M期检查

Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer复制标题

Wee1抑制剂Adavosertib (AZD1775) 联合吉西他滨和放疗治疗局部晚期胰腺癌患者的剂量递增试验

发表时间:2019-10-10

影响因子:28.2

作者: Kyle C. Cuneo

期刊:J. Clin. Oncol.

PURPOSE: AZD1775 (adavosertib) is an inhibitor of the Wee1 kinase. In this study, we built on our preclinical studies to evaluate the safety and efficacy of AZD1775 in combination with gemcitabine and radiation in patients with newly diagnosed locally advanced pancreatic cancer. PATIENTS AND METHODS: Thirty-four patients with locally advanced pancreatic cancer were enrolled with the intention to receive four 21-day cycles of gemcitabine (1,000 mg/m2 days 1 and 8) with AZD1775 (once daily on days 1, 2, 8, and 9). Cycles 2 and 3 were administered concurrently with radiation, and cycles 5 to 8 were optional. AZD1775 was dose escalated using a time-to-event continual reassessment method on the basis of the rate of dose-limiting toxicities within the first 15 weeks of therapy. The primary objective was to determine the maximum tolerated dose of AZD1775 given in conjunction with gemcitabine and radiation. Secondary objectives were to estimate overall and progression-free survival and determine pharmacodynamic activity of AZD1775 in surrogate tissues.

译文

用途:AZD1775(adavosertib)是Wee1激酶的抑制剂。在这项研究中,我们基于临床前研究来评估AZD1775联合吉西他滨和放疗在新近诊断为局部晚期胰腺癌患者中的安全性和有效性。患者和方法:招募了34例局部晚期胰腺癌患者,以接受吉西他滨的四个21天周期(1,000 mg / m2第1和8天)和AZD1775周期(第1、2、8,每天一次)和9)。周期2和3与放疗同时进行,周期5至8是可选的。根据治疗前15周内剂量限制性毒性的发生率,使用事件持续时间重新评估方法对AZD1775进行剂量递增。主要目的是确定吉西他滨和放疗联合给予的AZD1775的最大耐受剂量。次要目标是评估总体和无进展生存期,并确定替代组织中AZD1775的药效活性。