Li Qi, Yano Seiji, Ogino Hirokazu, Wang Wei, Uehara Hisanori, Nishioka Yasuhiko, Sone Saburo
Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima Graduate School, Tokushima, Japan
Clin Cancer Res. 2007 Oct 1;13(19):5918-25. doi: 10.1158/1078-0432.CCR-07-0501.
Malignant pleural mesothelioma (MPM) is an aggressive malignancy, which has a poor prognosis with a median survival of less than 1 year. The vascular endothelial growth factor (VEGF) has been reported to be an ideal therapeutic target, and a multitargeted antifolate, pemetrexed, has been clinically used for the treatment of MPM.
We examined the therapeutic efficacy of the antihuman VEGF neutralizing antibody, bevacizumab, in combination with pemetrexed against two different human MPM cells, EHMES-10 and MSTO-211H, orthotopically inoculated into severe combined immunodeficient mice.
Bevacizumab inhibited a VEGF-induced proliferation of the human endothelial cells in a dose-dependent manner, but it had no effect on the proliferation of the two MPM cell lines in vitro. The orthotopically inoculated EHMES-10 cells (VEGF high expressing) produced thoracic tumors and a large volume of bloody pleural effusion, whereas the MSTO-211H cells (VEGF low expressing) produced thoracic tumors and a small volume of bloody effusions. Treatment with bevacizumab effectively inhibited the production of thoracic tumors and dramatically prevented the production of pleural effusion by the EHMES-10 cells but not the MSTO-211H cells. Treatment with bevacizumab reduced the number of enlarged tumor-associated vessels and proliferating tumor cells. Moreover, treatment with bevacizumab in combination with pemetrexed more effectively suppressed the formation of the pleural effusion and prolonged the survival compared with the control and monotherapy in the EHMES-10 cell-bearing severe combined immunodeficient mice.
These results suggest that the combined use of bevacizumab and pemetrexed may therefore be promising for controlling the progression of MPM highly expressing VEGF.
恶性胸膜间皮瘤(MPM)是一种侵袭性恶性肿瘤,预后较差,中位生存期不到1年。血管内皮生长因子(VEGF)据报道是一个理想的治疗靶点,多靶点抗叶酸药物培美曲塞已在临床上用于治疗MPM。
我们检测了抗人VEGF中和抗体贝伐单抗联合培美曲塞对两种不同的人MPM细胞系EHMES - 10和MSTO - 211H原位接种到严重联合免疫缺陷小鼠体内后的治疗效果。
贝伐单抗以剂量依赖方式抑制VEGF诱导的人内皮细胞增殖,但对两种MPM细胞系的体外增殖无影响。原位接种的EHMES - 10细胞(VEGF高表达)产生胸内肿瘤和大量血性胸腔积液,而MSTO - 211H细胞(VEGF低表达)产生胸内肿瘤和少量血性胸腔积液。贝伐单抗治疗有效抑制了EHMES - 10细胞胸内肿瘤的产生,并显著阻止了胸腔积液的产生,但对MSTO - 211H细胞无效。贝伐单抗治疗减少了肿大的肿瘤相关血管数量和增殖的肿瘤细胞数量。此外,在携带EHMES - 10细胞的严重联合免疫缺陷小鼠中,与对照和单一疗法相比,贝伐单抗联合培美曲塞治疗更有效地抑制了胸腔积液的形成并延长了生存期。
这些结果表明,贝伐单抗和培美曲塞联合使用可能对控制高表达VEGF的MPM进展有前景。