PHASE I STUDY OF FLAVOPIRIDOL WITH IMATINIB MESYLATE (STI1571, GLEEVEC)

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这项研究提出，同时中断细胞周期和生存信号通路将发挥协同抗白血病作用的Bcr/abl+恶性肿瘤，这种策略可能是有效的，至少在一个子集的STI 571耐药细胞通过Bcr/Abl扩增或蛋白表达增加。 Flavopiridol是一种半合成的黄酮，来源于类黄酮rohitukine，其作为多种细胞周期蛋白依赖性激酶（CDK）的有效抑制剂。 Flavopiridol已被证明具有抗血管生成活性，并且是第一个进入人体临床试验的药理学CDK抑制剂。 正如其作用机制所预期的那样，flavopiridol是一种有效的细胞周期穿越抑制剂，可触发G1和G2 M期的细胞周期阻滞。 Flavopiridol也是凋亡的有效诱导剂，特别是在恶性造血细胞中。 最近，flavopiridol已被证明作为一个转录调节剂作为其抑制CDK 9/TEFb复合物的能力的结果。几个理论上的考虑支持的概念，flavopiridol与伊马替尼组合可能会导致在Bcr/Abl+细胞的致死率显着增强。 首先，flavopiridol对人白血病细胞具有广泛的活性，并在亚微摩尔浓度下诱导此类细胞的凋亡。 其次，先前的研究表明，同时破坏生存信号通路和细胞周期调节通路导致细胞死亡的显著增加。 最近的研究表明，MEK抑制剂与伊马替尼在Bcr/Abl+细胞中协同作用。 因此，当与Bcr/Abl破坏（例如，伊马替尼）可能通过类似的机制导致协同抗白血病作用。 在这方面，最近的研究表明，在Bcr/Abl+细胞中同时施用flavopiridol与伊马替尼导致线粒体损伤、casapase活化和细胞凋亡的显著增加。 这些事件与信号转导/细胞周期调节途径的多种扰动相关，包括Mcl-1、细胞周期蛋白D1、磷酸化Creb的下调、pRb的裂解和应激相关JNK激酶的激活。 值得注意的是，在表现出Bcr/Abl表达增加的伊马替尼耐药Bcr/Abl+细胞中观察到flavopiridol和伊马替尼之间的协同相互作用。 这些发现提出了这样的可能性，即flavopiridol与伊马替尼联合使用可能至少对通过Bcr/Abl扩增或蛋白表达增加而对伊马替尼耐药的Bcr/Abl+细胞亚群有效。 根据入组时的外周血和骨髓原始细胞计数，将患者入组两组之一。研究药物将以适当的剂量给药，并对患者进行监测。将获得用于药代动力学/药效学（PK/PD）分析的病理标本、病历、数据、血液标本。 如果患者在研究外接受治疗，则将进行除PK/PD外的所有检查/程序。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study proposes that simultaneously interrupting cell cycle and survival signaling pathways will exert synergistic antileukemic effects in Bcr/abl+ malignancies and that this strategy may be effective in at least a subset of STI571-resistant cells through Bcr/Abl amplification or increased protein expression. Flavopiridol is a semisynthetic flavone, derived from the flavonoid rohitukine, which acts as potent inhibitor of multiple cyclin-dependent kinases (CDKs). Flavopiridol has been shown to exhibit anti-angiogenic activity and is the first of the pharmacologic CDK inhibitors to enter clinical trials in humans. As anticipated from its mechanism of action, flavopiridol is a potent inhibitor of cell cycle traverse, triggering cell cycle arrest in G1 as well as in G2M. Flavopiridol is also an effective inducer of apoptosis, particularly in malignant hematopoietic cells. Recently, flavopiridol has been shown to act as a transcriptional regulator as a consequence of its ability to inhibit the CDK9/TEFb complex. Several theoretical considerations support the concept that combining flavopiridol with imatinib may result in a significant potentiation of lethality in Bcr/Abl+ cells. First, flavopiridol is broadly active against human leukemia cells, and induces apoptosis in such cells at sub-micromolar concentrations. Second, previous studies indicate that simultaneous disruption of a survival signaling pathway and disruption of a cell cycle regulatory pathway results in a pronounced increase in cell death. More recent studies indicate that MEK inhibitors interact synergistically with imatinib in Bcr/Abl+ cells. Thus, CDK inhibition by flavopiridol may, when combined with Bcr/Abl disruption (e.g., imatinib) may lead to synergistic antileukemic effects through a similar mechanism. In this regard, recent studies indicate that simultaneous administration of flavopiridol with imatinib in Bcr/Abl+ cells leads to a marked increase in mitochondrial damage, casapase activation, and apoptosis. Such events were associated with multiple perturbations in signaling/cell cycle regulatory pathways, including down-regulation of Mcl-1, cyclin D1, phospho-Creb, cleavage of pRb, and activation of the stress-related JNK kinase. Significantly, synergistic interactions between flavopiridol and imatinib were observed in imatinib-resistant Bcr/Abl+ cells exhibiting increased Bcr/Abl expression. Such findings raise the possibility that combining flavopiridol with imatinib may be effective against at least the subset of Bcr/Abl+ cells that are resistant to imatinib through Bcr/Abl amplification or increased protein expression. Patients are enrolled into one of two groups based upon the peripheral blood and bone marrow blast count at the time of enrollment. Study drugs will be administered in the appropriate dosage and patients will be monitored. Pathology specimens, medical records, data, blood specimens for pharmacokinetic/pharmacodynamic (PK/PD) analysis will be obtained. All tests/procedures, except the PK/PD would be performed if patients were treated off-study.