Protein Kinase Antagonists: Preclinical and Clinical

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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),.