Cell cycle-dependent and schedule-dependent antitumor effects of sorafenib combined with radiation
Cell cycle-dependent and schedule-dependent antitumor effects of sorafenib combined with radiation
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DOI：
10.1158/0008-5472.can-07-1473
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
El-Deiry, Wafik S.
中科院分区：
文献类型：
--
作者：
Plastaras, John P.;Kim, Seok-Hyun;El-Deiry, Wafik S.
抗肿瘤药物索拉非尼（BAY 43-9006）是一种多激酶抑制剂，靶向丝氨酸-苏氨酸激酶B-Raf以及几种酪氨酸激酶。鉴于索拉非尼的许多分子靶点，存在几种潜在的抗癌作用机制，包括诱导细胞凋亡、细胞抑制和抗血管生成。我们观察到索拉非尼在几种人肿瘤细胞系的活力测定中具有广泛的活性，但仅在一些细胞系中选择性地诱导凋亡。索拉非尼被发现在大多数测试的细胞系中降低Mcl-1水平，但这种降低与凋亡敏感性无关。索拉非尼减缓细胞周期进程，并防止辐照细胞达到G2-M并在G2-M积累。在同步化的细胞中，索拉非尼引起可逆的G1延迟，这与细胞周期蛋白D1、Rb和Rb磷酸化水平的降低有关。虽然索拉非尼不影响固有的放射敏感性使用体外集落形成试验，它显着降低集落大小。在小鼠HCT 116异种移植肿瘤生长延迟实验中，索拉非尼以时间表依赖性方式改变辐射反应。放射治疗后序贯索拉非尼被发现与最大的肿瘤生长延迟相关。本研究为序贯分次放疗联合索拉非尼治疗胃肠道及其他恶性肿瘤的临床试验奠定了基础。
The antineoplastic drug sorafenib (BAY 43-9006) is a multikinase inhibitor that targets the serine-threonine kinase B-Raf as well as several tyrosine kinases. Given the numerous molecular targets of sorafenib, there are several potential anticancer mechanisms of action, including induction of apoptosis, cytostasis, and antiangiogenesis. We observed that sorafenib has broad activity in viability assays in several human tumor cell lines but selectively induces apoptosis in only some lines. Sorafenib was found to decrease Mcl-1 levels in most cell lines tested, but this decrease did not correlate with apoptotic sensitivity. Sorafenib slows cell cycle progression and prevents irradiated cells from reaching and accumulating at G2-M. In synchronized cells, sorafenib causes a reversible G, delay, which is associated with decreased levels of cyclin D1, Rb, and phosphorylation of Rb. Although sorafenib does not affect intrinsic radiosensitivity using in vitro colony formation assays, it significantly reduces colony size. In HCT116 xenograft tumor growth delay experiments in mice, sorafenib alters radiation response in a schedule-dependent manner. Radiation treatment followed sequentially by sorafenib was found to be associated with the greatest tumor growth delay. This study establishes a foundation for clinical testing of sequential fractionated radiation followed by sorafenib in gastrointestinal and other malignancies.