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，通过烷基磷脂（包括哌立福新）间接修饰蛋白激酶信号通路。完成了UCN-01的I期试验，第一个疗程连续输注72小时，然后每四周输注一半剂量，并提供了初步结果（ASCO，1999）。剂量限制性毒性包括肺部、高血糖症和乳酸酸中毒。MTD为42.5 mg/M2/d x 3。其他毒性包括疲乏、低血压和肌痛。初步研究显示，与小鼠、大鼠和犬的临床前研究相比，UCN-01的人体药理学存在显著差异。具体地，人具有与血浆α酸性糖蛋白的高亲和力结合，因此具有非常长的药物半衰期（T1/2 > 1000 hr）并耐受高得多的药物浓度。未来的计划是考虑未来I期更短的输注时间，并与标准化疗药物联合。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。正在实现超过2 μ M的峰值浓度，在给药期间正在连续减少剂量，预计在2000财政年度期间完成qd x 3和每周一次的时间表。初始剂量水平的哌立福新，作为负荷剂量和持续每日口服给药给药，似乎耐受良好。2000财政年度还将制定一项在头颈部鳞状细胞癌患者中间歇性IV推注flavopiridol的II期方案。 - 细胞信号传导、化疗药物、药代动力学、药理学、蛋白激酶、-人体受试者和人体组织、液体、细胞等。

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 was undertaken during the project period listed. A phase I trial of UCN-01 administered as a 72 hr continuous infusion for the first course, followed by half the dose every four weeks was completed, and preliminary results presented(ASCO, 1999) Forty-seven patients were treated on the intial trial. Dose limiting toxicities included pulmonary, hyperglycemia, and lactic acidosis. The MTD is 42.5 mg/M2/d x 3. Additional toxicities included fatigue, hypotension, and myalgias. Initial studies revealed a marked difference in the human pharmacology of UCN-01, in comparison to pre- clinial studies in mice, rats, and dogs. Specifically, humans have high affinity binding to plasma alpha acidic glycoprotein, and therefore have very long half times (T1/2 > 1000 hr) of the drug and tolerate much higher concentrations of drug. Future plans are to consider future Phase Is of more brief infusion duration and in combination with standard chemotherapy agents. 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 are being undertaken, with completion of qd x 3 and once weekly schedules anticipated during FY2000. Initial dose levels of perifosine, administered as a loading dose and a continued daily oral dosing appear well tolerated. A Phase II protocol of intermittent IV bolus dosing of flavopiridol in patients with squamous carcinoma of the head and neck will be developed also in FY2000. - cell signaling, chemotherapeutics, pharmacokinetics, pharmacology, protein kinase, - Human Subjects & Human Tissues, Fluids, Cells, etc.