Protein Kinase Antagonists: Preclinical and Clinical

该项目领域正在研究两种蛋白激酶拮抗剂flavopiridol和UCN-01的初始I期临床试验。此外，在所列项目期间，探索了通过烷基磷脂（包括哌立福辛、PS341蛋白体抑制和组蛋白脱乙酰酶抑制（MS 275））修饰蛋白激酶信号传导途径的间接方法。 基于对造血肿瘤有效性的临床前研究，已经进行了一项使用间歇推注给药flavopiridol的I期试验。当以qd x 5方案给药时，初始MTD为37 mg/M2/d。 在给药期间连续降低剂量以增加达到的峰值浓度，定义为50 mg/M2/d × 3和62.5 mg/M2/d，每个方案为qd × 3。峰值浓度连续增加至4 - 5 uM水平，但没有造血模型中引起细胞凋亡的浓度那么高。flavopiridol的未来计划将集中在难治性头颈癌患者的II期试验中明确定义药物影响分子终点（如细胞周期蛋白D1表达）的能力。对UCN-01的研究已经阐明，该试剂的重要靶点是检查点激酶chk 1，这可以部分解释该药物使细胞对DNA损伤剂作用敏感的能力（J. Biol. Chem 275：5600，2000）。初始剂量水平的哌立福辛，作为负荷剂量和持续每日口服给药，似乎耐受良好，生物学研究表明，诱导p21作为药物引起细胞周期阻滞可能代表一个重要的终点。将在2000年底和2001年初制定临床方案，探索蛋白体抑制剂PS341和组蛋白脱酰酶抑制剂MS 275通过上调p21间接调节细胞周期蛋白依赖性激酶活性的能力。

This project area is studying in initial Phase I clinical trials two protein kinase antagonists, flavopiridol and UCN-01. In addition, indirect means of modifying protein kinase signalling pathways through alkylphospholipids including Perifosine, PS341 proteosome inhibition, and histone deacetylase inhibition(MS275) were explored during the project period listed. A Phase I trial utilizing intermittent bolus dosing of flavopiridol, based on preclinical studies of efficiacy in hematopoietic neoplasms has been undertaken. The initial MTD when administered on a qd x 5 schedule was 37 mg/M2/d. Concentrations at peak in excess of 2 uM are being achieved.Successive decreases in the period of dosing were undertaken in an effort to increase the peak concentrations achieved, with definition of 50 mg/M2/d x3, and 62.5 mg/M2/d, each on a qd x 3 schedule. Successive increases in peak concentration to the 4 - 5 uM level were achieved, but not as high as those concentrations causing apoptosis in the hematopoetic models. Future plans with flavopiridol will focus on a aclear definition in a Phase II trial in patients with refractory Head and Neck carcinoma of the ability of the drug to affect a molecular endpoint such as cyclin D1 expression. Studies with UCN-01 have elucidated that an important target for the agent is the checkpoint kinase chk1, and this may explain in part the ability of the drug to sensitize cells to DNA damaging agent action(J. Biol. Chem 275: 5600, 2000). Initial dose levels of perifosine, administered as a loading dose and a continued daily oral dosing appear well tolerated, and biological studies suggest that induction of p21 as the drug causes cell cycle arrest may represent an important endpoint. Clinical protocols exploring the capacity of the proteosome inhibitor PS341 and the histone deacylase inhibitor MS275 to modulate cyclin dependent kinase activity indirectly through upregulation of p21 will be developed during late 2000 and early 2001.