Jiang Feng, Zhang Xuepeng, Kalkanis Steven N, Zhang Zhenggang, Yang Hongyan, Katakowski Mark, Hong Xin, Zheng Xuguang, Zhu Zhenping, Chopp Michael
Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
Photochem Photobiol. 2008 Jan-Feb;84(1):128-37. doi: 10.1111/j.1751-1097.2007.00208.x.
The objective of this study was to evaluate the effects of combination therapy with photodynamic therapy (PDT) and a novel antiangiogenic regimen using monoclonal antibodies against both vascular endothelial growth factor receptors (VEGFR)-1 (MF1) and VEGFR-2 (DC101) on intracranial glioblastoma xenografts in nude mice. Nude mice bearing intracerebral U87 glioblastoma were treated with PDT and the antiangiogenic regimen (MF1 and DC101) either alone or in combination, while those left untreated served as tumor controls. Tumor volume and animal survival time were analyzed to evaluate the outcome of different treatment modalities. In addition, the immunohistochemical expression of VEGF in the brain adjacent to the tumor, von Willebrand factor (vWF), apoptotic, and proliferative markers in the tumor area were examined. PDT or MF1 + DC101 alone significantly reduced the tumor volume and prolonged the survival time of glioma-implanted animals. Combined therapy markedly reduced tumor volume and increased survival time with significantly better outcomes than both monotherapies. Both vWF and VEGF levels significantly increased after PDT while they both significantly decreased after antiangiogenic treatment, compared with no treatment. PDT plus antiangiogenic treatment led to significant decreases in both vWF and VEGF expression, compared with PDT alone. Either PDT or antiangiogenic treatment alone significantly increased tumor cell apoptosis compared with no treatment, while combination therapy resulted in further augmentation of apoptosis. Antiangiogenic treatment with or without PDT significantly decreased tumor cell proliferation, compared with either no treatment or PDT alone. In summary, we demonstrate both significant inhibition of tumor growth and extended survival of mice treated by the combination therapy with PDT and antiangiogenic agents, compared with each single treatment, suggesting that the combination therapy may be a promising strategy to improve clinical outcomes in glioblastoma.
本研究的目的是评估光动力疗法（PDT）与一种新型抗血管生成方案联合治疗的效果，该抗血管生成方案使用针对血管内皮生长因子受体（VEGFR）-1（MF1）和VEGFR-2（DC101）的单克隆抗体，对裸鼠颅内胶质母细胞瘤异种移植瘤的影响。将携带脑内U87胶质母细胞瘤的裸鼠单独或联合使用PDT和抗血管生成方案（MF1和DC101）进行治疗，而未接受治疗的裸鼠作为肿瘤对照。分析肿瘤体积和动物存活时间以评估不同治疗方式的结果。此外，还检测了肿瘤邻近脑组织中VEGF的免疫组化表达、肿瘤区域的血管性血友病因子（vWF）、凋亡和增殖标志物。单独使用PDT或MF1 + DC101均可显著减小肿瘤体积并延长胶质瘤植入动物的存活时间。联合治疗显著减小了肿瘤体积并延长了存活时间，其结果明显优于两种单一疗法。与未治疗相比，PDT后vWF和VEGF水平均显著升高，而抗血管生成治疗后两者均显著降低。与单独使用PDT相比，PDT加抗血管生成治疗导致vWF和VEGF表达均显著降低。与未治疗相比，单独使用PDT或抗血管生成治疗均可显著增加肿瘤细胞凋亡，而联合治疗导致凋亡进一步增加。与未治疗或单独使用PDT相比，无论是否使用PDT的抗血管生成治疗均显著降低肿瘤细胞增殖。总之，我们证明与每种单一治疗相比，PDT和抗血管生成药物联合治疗可显著抑制肿瘤生长并延长小鼠存活时间，这表明联合治疗可能是改善胶质母细胞瘤临床结果的一种有前景的策略。
