Appleyard Maria Virginia C L, O'Neill Mary A, Murray Karen E, Paulin Fiona E M, Bray Susan E, Kernohan Neil M, Levison David A, Lane David P, Thompson Alastair M
Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
Int J Cancer. 2009 Jan 15;124(2):465-72. doi: 10.1002/ijc.23938.
We sought to determine whether seliciclib (CYC202, R-roscovitine) could increase the antitumor effects of doxorubicin, with no increase in toxicity, in an MCF7 breast cancer xenograft model. The efficacy of seliciclib combined with doxorubicin was compared with single agent doxorubicin or seliciclib administered to MCF7 cells and to nude mice bearing established MCF7 xenografts. Post-treatment cells and tumors were examined by cell cycle analysis, immunohistochemistry and real-time PCR. Seliciclib significantly enhanced the antitumor effect of doxorubicin without additional murine toxicity. MIB1 (ki67) immunohistochemistry demonstrated reduced proliferation with treatment. The levels of p21 and p27 increased after treatment with doxorubicin or seliciclib alone or in combination, compared to untreated controls. However, no changes in p53 protein (DO1, CM1), survivin or p53 phosphorylation (SER15) were observed in treated tumors compared with controls. In conclusion, the CDK inhibitor seliciclib (R-roscovitine) enhances the antitumor effect of doxorubicin in MCF7 tumors without increased toxicity with a mechanism that involves cell cycle arrest rather than apoptosis.
我们试图确定在MCF7乳腺癌异种移植模型中，塞利西利布（CYC202，R-罗库溴铵）能否增强阿霉素的抗肿瘤作用，同时不增加毒性。将塞利西利布与阿霉素联合使用的疗效，与单独给予阿霉素或塞利西利布处理MCF7细胞以及移植了MCF7异种移植物的裸鼠的疗效进行了比较。通过细胞周期分析、免疫组织化学和实时PCR对处理后的细胞和肿瘤进行检测。塞利西利布显著增强了阿霉素的抗肿瘤作用，且未增加小鼠毒性。MIB1（ki67）免疫组织化学显示治疗后增殖减少。与未处理的对照组相比，单独或联合使用阿霉素或塞利西利布治疗后，p21和p27水平升高。然而，与对照组相比，在治疗的肿瘤中未观察到p53蛋白（DO1，CM1）、生存素或p53磷酸化（SER15）的变化。总之，CDK抑制剂塞利西利布（R-罗库溴铵）通过涉及细胞周期停滞而非凋亡的机制，增强了阿霉素对MCF7肿瘤的抗肿瘤作用，且不增加毒性。
