Protein Kinase Antagonists: Preclinical and Clinical

该项目领域扩展了该小组先前的工作，推进了新型蛋白激酶拮抗剂的临床前开发和临床应用。在研究期间，发表了72小时连续IV输注UCN-01的完整I期结果（J. Clin. Oncol. 19：2319，2001）。继续使用哌立福新（一种通过增加p21（通过尚未确定的途径）调节CDK功能的调节剂）进行方案研究。组蛋白脱乙酰酶抑制剂MS-275（其也引起细胞周期停滞，同时抑制CDK并增加p21）的I期试验已经开始，临床前实验将增强的TGF-β表达定义为该药物生物学效应的潜在标志物（Cancer Research 61：931，2001）。其他方案工作集中在flavopiridol上。基于造血肿瘤有效性的临床前研究，使用间歇推注给药flavopiridol的I期试验已经完成，最终报告正在编写中。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，以努力增加达到的峰值浓度，定义为50 mg/M2/d x3和62.5 mg/M2/d x1，每三周一次。实现了峰值浓度连续增加至4 - 5 μ M水平，但没有造血模型中引起细胞凋亡的那些浓度高。flavopiridol的未来计划将集中在一个明确的定义，在一个II期试验中，难治性头颈癌患者的药物的能力，影响分子终点，如细胞周期蛋白D1的表达。在理解flavopiridol的腹泻副作用方面的进展，阐明了该药物对结肠上皮细胞系中的氯离子分泌具有直接刺激作用（Clinical Cancer Research 7：343，2001）。

This project area is extending the prior work of this group which advances the pre-clinical development and clinical application of novel protein kinase antagonists. During the study period, completed Phase I results of a 72 hr continuous IV infusion UCN-01 were published ( J. Clin. Oncol. 19: 2319, 2001). Protocol efforts with perifosine, a modulator of CDK function by increasing p21(by an as yet undefined pathway) were continued. A Phase I trial of the histone deacetylase inhibitor MS-275, which also causes cell cycle arrest with inhibition of CDKs and also increase in p21 was opened, with pre-clinical experiments defining enhanced TGF-beta expression as a potential marker for this drug's biologic effect (Cancer Research 61: 931, 2001). Other protocol efforts centered on flavopiridol. A Phase I trial utilizing intermittent bolus dosing of flavopiridol, based on preclinical studies of efficiacy in hematopoietic neoplasms has been completed and a final report in preparation. 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 x1, each on a every three week 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 a clear 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. Progress in understanding the diarreal side effects of flavopiridol with the elucidation that the drug has a direct stimulatory effect on chloride ion secretion in a colon epithelial cell line (Clinical Cancer Research 7:343, 2001),.