Hahntow I N, Schneller F, Oelsner M, Weick K, Ringshausen I, Fend F, Peschel C, Decker T
Department of Medicine, Technical University of Munich, Munich, Germany.
Leukemia. 2004 Apr;18(4):747-55. doi: 10.1038/sj.leu.2403295.
A new class of cell cycle inhibitors is currently entering clinical trials. These drugs exert their activity by inhibition of cyclin-dependent kinases (cdk) and induce cell cycle arrest and apoptosis in cancer cells. Roscovitine, a cdk2-inhibitor that is in preclinical evaluation, induced apoptosis in B-CLL cells at doses that were not cytotoxic for normal human B cells. At 20 microM, Roscovitine induced apoptosis in 21 of 28 B-CLL samples and was equally effective in zap-70-positive or -negative samples. Caspase-3 was cleaved in B-CLL cells exposed to Roscovitine and the pancaspase inhibitor z.VAD.fmk-blocked Roscovitine-induced apoptosis. Expression of the proapoptotic protein Bak was increased and Bax cleavage and conformational change was observed in Roscovitine-treated B-CLL cells. Antiapoptotic proteins Mcl-1 and XIAP were downregulated, but the expression of Bcl-2 remained unchanged. In contrast to previous reports in cancer cell lines, Roscovitine treatment was not accompanied by nuclear accumulation of p53. Cyc202 (R-Roscovitine) is in early clinical trials in cancer patients. Given its powerful effects on zap-70-positive and -negative B-CLL cells, but not on normal lymphocytes, Roscovitine might be an attractive drug to be tested in this incurable disease.
一类新型细胞周期抑制剂目前正在进入临床试验阶段。这些药物通过抑制细胞周期蛋白依赖性激酶（cdk）发挥作用，并诱导癌细胞的细胞周期停滞和凋亡。Roscovitine是一种处于临床前评估阶段的cdk2抑制剂，在对正常人B细胞无细胞毒性的剂量下可诱导B细胞慢性淋巴细胞白血病（B-CLL）细胞凋亡。在20微摩尔浓度下，Roscovitine可诱导28个B-CLL样本中的21个发生凋亡，且对zap-70阳性或阴性样本同样有效。在暴露于Roscovitine的B-CLL细胞中，半胱天冬酶-3被切割，而泛半胱天冬酶抑制剂z.VAD.fmk可阻断Roscovitine诱导的凋亡。在经Roscovitine处理的B-CLL细胞中，促凋亡蛋白Bak的表达增加，同时观察到Bax的切割和构象变化。抗凋亡蛋白Mcl-1和XIAP表达下调，但Bcl-2的表达保持不变。与之前在癌细胞系中的报道不同，Roscovitine处理并未伴随p53的核内积累。Cyc202（R-Roscovitine）正在癌症患者中进行早期临床试验。鉴于其对zap-70阳性和阴性B-CLL细胞具有强大作用，但对正常淋巴细胞无作用，Roscovitine可能是一种有吸引力的药物，可用于在这种无法治愈的疾病中进行测试。
