Shapiro Geoffrey I
Department of Medical Oncology and Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Clin Cancer Res. 2004 Jun 15;10(12 Pt 2):4270s-4275s. doi: 10.1158/1078-0432.CCR-040020.
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 II 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 II 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(max) 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.
黄酮哌啶醇是首个进入临床试验的细胞周期蛋白依赖性激酶（cdks）强效抑制剂。在大多数实体瘤细胞系和异种移植瘤中，黄酮哌啶醇可诱导细胞周期停滞并抑制肿瘤生长。这在临床结果中得到了体现：在多项II期试验中，有部分患者病情长期稳定，尽管观察到的缓解情况较少。黄酮哌啶醇与化疗药物表现出序列依赖性的细胞毒性协同作用。当化疗在黄酮哌啶醇之前进行时，这些效应最为显著。对于导致S期延迟的DNA损伤剂，黄酮哌啶醇介导的cdk抑制会破坏E2F-1的磷酸化，导致其活性不适当持续，从而诱导凋亡途径。这一机制已在吉西他滨和黄酮哌啶醇序贯给药的I期试验中得到应用，并产生了有前景的结果。黄酮哌啶醇与紫杉烷类药物也具有协同作用。黄酮哌啶醇对细胞周期蛋白B-cdk1的抑制作用加速了与紫杉烷诱导的细胞死亡相关的异常有丝分裂的退出，并降低了生存素的磷酸化，防止其稳定以及紫杉烷暴露后它所提供的细胞保护作用。多西他赛和黄酮哌啶醇的序贯联合用药已在晚期非小细胞肺癌患者的I期试验中进行了研究，一项随机II期研究正在进行中。最初使用的黄酮哌啶醇给药方案是长时间持续输注，根据肿瘤细胞系的结果，这种给药方式可产生纳摩尔水平的药物，被认为能够实现cdk抑制。最近发现，微摩尔浓度可能更有效，现在已采用能达到更高C(max)的更短输注时间。负荷剂量后维持输注也在研发中，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。
