Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma
Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma
复制标题
DOI：
10.3892/or_00000720
复制
发表时间：
2010-04-01
期刊：
影响因子：
4.2
通讯作者：
Matsuda, Hideki
中科院分区：
文献类型：
--
作者：
Kondo, Norio;Tsukuda, Mamoru;Matsuda, Hideki
表皮生长因子受体（EGFR）及其相关家族成员。HER-2，在多种恶性肿瘤患者中常同时过表达，两者联合可协同促进癌细胞生长和生存。已知EGFR和HER-2的异源二聚化可产生强烈的增殖信号。拉帕替尼（GW572016）是一种口服小分子药物，可作为EGFR和HER-2酪氨酸激酶的可逆抑制剂。在本研究中，我们在体外和体内评价了拉帕替尼对头部和斑点鳞状细胞癌（HNSCC）细胞系的抗肿瘤作用。在体内，我们检查了拉帕替尼和顺铂或紫杉醇联合治疗的抗肿瘤效果。体外实验表明，拉帕替尼对HNSCC细胞有抗增殖作用。暴露于拉帕替尼24小时后，拉帕替尼的IC50在13.6 ~ 60.2 μ M之间。拉帕替尼体外增殖试验的结果与EGFR或HER-2的表达没有关联。在体内，拉帕替尼显示出抗肿瘤活性，并在移植了YCU-H891细胞的裸鼠中诱导细胞凋亡。拉帕替尼对血管生成无明显抑制作用。拉帕替尼与顺铂或紫杉醇联合治疗主要通过诱导细胞凋亡增强抗肿瘤活性。仅在拉帕替尼与紫杉醇联合治疗时观察到抗血管生成的抑制作用（与对照对照相比）。这些结果表明：1)拉帕替尼在体内外均具有抗肿瘤作用；Ii)拉帕替尼联合顺铂或紫杉醇可能更有效；iii)拉帕替尼可能为HNSCC患者提供有用的临床益处。
The epidermal growth factor receptor (EGFR) and a related family member. HER-2, are often overexpressed simultaneously in patients with a variety of malignant tumors, and the combination may cooperatively promote cancer cell growth and Survival. Heterodimerization of EGFR and HER-2 has been known to create intense proliferative signals. Lapatinib (GW572016) is a small molecule that is administrated orally and functions as a reversible inhibitor of both EGFR and HER-2 tyrosine kinases. In the present study, we evaluated the antitumor effect of lapatinib on head and fleck squamous cell carcinoma (HNSCC) cell lines in vitro and in vivo. In vivo we examined the antitumor effects of combined treatment with lapatinib and either cisplatin of paclitaxel. In vitro lapatinib displayed antiproliferative effects on HNSCC cells. The IC50 of lapatinib ranged between 13.6 and 60.2 mu M after 24-h exposure to lapatinib. A con-elation was not observed between results of in vitro proliferation assays for lapatinib and the expression of EGFR or HER-2. In vivo lapatinib displayed antitumor activity, and induced apoptosis in nude mice bearing an established xenograft of YCU-H891 cells. Lapatinib did not significantly inhibit angiogenesis. Combination treatment of lapatinib with cisplatin or paclitaxel enhanced antitumor activity mainly by inducing apoptosis. Inhibition of antiangiogenesis was observed only for combination treatment of lapatinib with paclitaxel (compared to vehicle control). These results Suggest that: i) lapatinib has antitumor effects in vitro and in vivo; ii) lapatinib may be more effective in combination with cisplatin or paclitaxel; and iii) lapatinib might provide useful Clinical benefits to HNSCC patients.