In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine)
In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine)
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DOI：
10.1002/ijc.10738
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发表时间：
2002-12-10
影响因子：
6.4
通讯作者：
Lane, DP
中科院分区：
文献类型：
--
作者：
McClue, SJ;Blake, D;Lane, DP
已经提出CDK 2抑制剂作为有效的抗癌治疗剂。我们在这里表明，CYC 202（R-roscovitine）是一个有效的抑制剂的重组CDK 2/细胞周期蛋白E激酶活性（IC 50 = 0.10 μ M）的平均细胞毒性IC 50为15.2 μ M的19人肿瘤细胞系的面板，我们也证明了选择性快速增殖细胞非增殖细胞。在Lovo结肠直肠癌细胞中对CYC 202的细胞周期影响的研究表明，主要影响不是预测的周期一部分的停滞，而是诱导细胞周期所有区室的细胞死亡。小鼠静脉给药的最大耐受剂量超过20 mg/kg。小鼠经口给药时，耐受剂量高达2，000 mg/kg。在对携带Lovo人结肠直肠肿瘤的裸鼠重复腹膜内给予100 mg/kg（每日3次，持续5天）后，CYC 202诱导了显著的抗肿瘤作用，与对照组相比，肿瘤生长减少了45%。使用口服给予CYC 202（500 mg/kg，每日3次，持续4天）处理的人子宫异种移植物MESSA-DX 5的第二个实验也显示出肿瘤生长速率的显著降低（62%）。这些数据显示了酶和细胞效能以及抗肿瘤活性，证实了CDK 2抑制剂如CYC 202作为抗癌药物的潜力。(C)2002 Wiley-Liss，Inc.
CDK2 inhibitors have been proposed as effective anti-cancer therapeutics. We show here that CYC202 (R-roscovitine) is a potent inhibitor of recombinant CDK2/cyclin E kinase activity (IC50 = 0.10 muM) with an average cytotoxic IC50 of 15.2 muM in a panel of 19 human tumour cell lines, and we also demonstrate selectivity for rapidly proliferating cells over non-proliferating cells. A study of the cell cycle effects of CYC202 in Lovo colorectal carcinoma cells showed that the major effect was not the predicted arrest in one part of the cycle, but rather an induction of cell death from all compartments of the cell cycle. The maximum tolerated dose given intravenously to mice was in excess of 20 mg/kg. Doses up to 2,000 mg/kg were tolerated when administered orally in mice. Following repeated intraperitoneal administration (3 times daily for 5 days) of 100 mg/kg to nude mice bearing the Lovo human colorectal tumour, CYC202 induced a significant antitumour effect with a 45% reduction in tumour growth compared to controls. A second experiment using the human uterine xenograft MESSA-DX5 treated with orally administered CYC202 (500 mg/kg 3 times daily for 4 days) also exhibited a significant reduction in the rate of growth of the tumour (62%). These data, showing enzyme and cellular potency together with antitumour activity, confirm the potential of CDK2 inhibitors such as CYC202 as anticancer drugs. (C) 2002 Wiley-Liss, Inc.