A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days.
A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days.
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DOI：
10.1038/sj.bjc.6603509
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发表时间：
2007-01-15
影响因子：
8.8
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中科院分区：
文献类型：
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Seliciclib（CYC202; R-roscovitine）是第一个进入临床试验的细胞周期蛋白依赖性激酶1、2、7和9的选择性口服生物可利用抑制剂。临床前研究表明，在广泛的人类肿瘤异种移植物中具有抗肿瘤活性。I期试验采用7天b.i.d. P.O. schedule. 21例患者（中位年龄62岁，范围：39-73岁）接受100、200和800 b.i.d.剂量治疗。在800 mg b.i.d.时观察到剂量限制性毒性; 3级疲劳、3级皮疹、3级低钠血症和4级低钾血症。其他毒性包括可逆性肌酐升高（2级）、可逆性3级肝功能异常和2级呕吐。在12名患者中进一步研究了800 mg剂量，其中3名患者有MAG 3肾图。第3天肌酐快速升高的1例患者肾灌注可逆性下降，第14天完全恢复，无提示肾小管损伤的变化。低钾血症阻止了进一步剂量递增。Seliciclib在1 - 4 h达到血药峰浓度，消除半衰期为2-5 h。在外周血单核细胞中未发现视网膜母细胞瘤蛋白磷酸化的抑制。没有观察到客观的肿瘤反应，但在8例患者中记录了疾病稳定;这在卵巢癌患者中持续了总共6个疗程（18周）。
Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range of human tumour xenografts. A phase I trial was performed with a 7-day b.i.d. p.o. schedule. Twenty-one patients (median age 62 years, range: 39–73 years) were treated with doses of 100, 200 and 800 b.i.d. Dose-limiting toxicities were seen at 800 mg b.i.d.; grade 3 fatigue, grade 3 skin rash, grade 3 hyponatraemia and grade 4 hypokalaemia. Other toxicities included reversible raised creatinine (grade 2), reversible grade 3 abnormal liver function and grade 2 emesis. An 800 mg portion was investigated further in 12 patients, three of whom had MAG3 renograms. One patient with a rapid increase in creatinine on day 3 had a reversible fall in renal perfusion, with full recovery by day 14, and no changes suggestive of renal tubular damage. Further dose escalation was precluded by hypokalaemia. Seliciclib reached peak plasma concentrations between 1 and 4 h and elimination half-life was 2–5 h. Inhibition of retinoblastoma protein phosphorylation was not demonstrated in peripheral blood mononuclear cells. No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer.