Protein Kinase Antagonists: Preclinical and Clinical

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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.