Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol
Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol
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DOI：
10.1158/1078-0432.ccr-040020
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发表时间：
2004-06-15
影响因子：
11.5
通讯作者：
Shapiro, GI
中科院分区：
文献类型：
--
作者：
Shapiro, GI
Flavopiridol是第一个进入临床试验的细胞周期蛋白依赖性激酶（cdks）抑制剂。在大多数实体瘤细胞系和异种移植物中，flavopiridol诱导细胞周期停滞和肿瘤生长抑制。这反映在临床结局中：在多项11期试验中，存在长期稳定疾病的患者子集，尽管很少观察到缓解。Flavopiridol显示与化疗剂的序列依赖性细胞毒性协同作用。当化疗先于flavopiridol时，这些效果最为显著。在施加S期延迟的DNA损伤剂的情况下，flavopiridol介导的cdk抑制破坏E2 F-1的磷酸化，导致其活性的不适当的持续，诱导凋亡途径。这一机制已在吉西他滨和flavopiridol序贯的I期试验中得到利用，该试验已产生了有希望的结果。Flavopiridol还与紫杉烷类化合物具有协同作用。flavopiridol抑制细胞周期蛋白B-cdk 1加速退出与紫杉烷诱导的细胞死亡相关的异常有丝分裂，并减少生存素的磷酸化，防止其稳定和紫杉烷暴露后提供的细胞保护。多西他赛和flavopiridol的序贯组合已在晚期非小细胞肺癌患者中进行了I期试验，一项随机11期研究正在进行中。最初的flavopiridol治疗方案是长时间连续输注，根据肿瘤细胞系的结果，产生纳摩尔水平的药物被认为能够实现cdk抑制。最近，已经发现微摩尔浓度可能更有效，并且现在已经采用实现更高C-a的更短输注。负荷后维持输注也在开发中，旨在实现持续的微摩尔药物水平。由于缺乏药效学终点来确认靶点抑制，临床试验仍然很复杂。
Flavopiridol is the first potent inhibitor of cyclin-dependent kinases (cdks) to reach clinical trial. In the majority of solid tumor cell lines and xenografts, flavopiridol induces cell cycle arrest and tumor growth inhibition. This is reflected in clinical outcomes: across multiple Phase 11 trials there are subsets of patients with prolonged stable disease, although few responses have been observed. Flavopiridol displays sequence-dependent cytotoxic synergy with chemotherapy agents. These effects are most marked when chemotherapy precedes flavopiridol. In the case of DNA-damaging agents that impose S-phase delay, flavopiridol-mediated cdk inhibition disrupts the phosphorylation of E2F-1, leading to inappropriate persistence of its activity, inducing apoptotic pathways. This mechanism has been exploited in a Phase I trial of sequential gemcitabine and flavopiridol that has produced promising results. Flavopiridol is also synergistic with taxanes. Inhibition of cyclin B-cdk1 by flavopiridol accelerates exit from an abnormal mitosis associated with taxane-induced cell death and reduces the phosphorylation of survivin, preventing its stabilization and the cellular protection it affords after taxane exposure. The sequential combination of docetaxel and flavopiridol has been investigated in a Phase I trial in patients with advanced non-small cell lung cancer, and a randomized Phase 11 study is under way. Initial schedules of flavopiridol used prolonged continuous infusions that produced nanomolar levels of drug thought to be capable of achieving cdk inhibition based on results in tumor cell lines. Recently, it has been discovered that micromolar concentrations are likely to be more effective, and shorter infusions that achieve a higher C-a have now been adopted. Loading followed by maintenance infusions are also under development, designed to achieve sustained micromolar drug levels. Clinical trials remain complicated by the absence of pharmacodynamic end points to confirm target inhibition.