Protein Kinase Antagonists: Preclinical and Clinical

本项目领域是对本课题组前期工作的延伸，旨在推进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，完成了72小时连续静脉输注UCN-01的I期结果（J. clinin）。中华医学杂志19:2319,2001)。通过增加p21（通过尚未确定的途径）来调节CDK功能的perifosine的方案努力继续进行。组蛋白去乙酰化酶抑制剂MS-275也通过抑制CDKs和增加p21导致细胞周期阻滞，临床前实验确定tgf - β表达增强是该药物生物学效应的潜在标志（Cancer Research 61: 931, 2001）。其他方案的努力集中在黄匹吡醇上。基于对造血肿瘤疗效的临床前研究，一项利用黄吡醇间歇给药的I期试验已经完成，最终报告正在准备中。初始MTD为37 mg/M2/d。已达到峰值浓度超过2um。在给药期间进行连续减少，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。在造血模型中，峰值浓度连续增加至4 - 5um水平，但没有达到引起细胞凋亡的浓度。黄匹立多的未来计划将集中于在难治性头颈癌患者的II期试验中明确定义该药物影响细胞周期蛋白D1表达等分子终点的能力。黄旋吡醇腹泻副作用的研究进展，阐明该药物对结肠上皮细胞系氯离子分泌有直接刺激作用（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),.