Glioma-Treatment with PDT and Anti-Angiogenic Agents

描述（由申请人提供）：我们提出测试一种新的假设，即在非肿瘤组织中诱导的血管生成独立于肿瘤，有助于肿瘤的生长。因此，如果治疗肿瘤的治疗性干预诱导邻近非肿瘤组织中的血管生成，则这种血管生成增加了肿瘤从残留肿瘤细胞再生长的可能性。我们建议在裸鼠的人脑胶质瘤模型中验证这一假设。所采用的抗肿瘤治疗是使用Photofrin作为光敏剂的光动力疗法（PDT）。在具体目标A中，测试了正常脑对PDT的血管生成反应，并分析了在PDT诱导的血管生成脑中植入肿瘤的效果。作为在特定目标A中进行的实验的逻辑结果，我们在特定目标B中测试使用PDT和抗血管生成剂联合治疗小鼠脑中的U87人胶质瘤的效果。我们预计，与单独治疗相比，联合治疗将显著降低肿瘤再生长的速率，从而延长动物的寿命。所用的抗血管生成剂是针对血管内皮生长因子受体（VEGFR1和VEGFR2）的抗体。如果我们是正确的，内源性脑血管生成有助于肿瘤的再生长，那么我们的研究对使用大多数形式的抗肿瘤药物治疗脑肿瘤具有重要意义。因此，使用抗血管生成和直接杀肿瘤治疗的组合可以转化为改善的治疗机会。

DESCRIPTION (provided by applicant): We propose to test a novel hypothesis that angiogenesis in non-tumor tissue induced independently of tumor, contributes to the growth of tumor. Thus if a therapeutic intervention to treat tumor induces angiogenesis in adjacent non-tumor tissue, this angiogenesis increases the likelihood of tumor regrowth from residual tumor cells. We propose to test this hypothesis in a model of human glioma in the nude mouse. The anti tumor treatment employed is photodynamic therapy (PDT) using Photofrin as the photosensitizer. In specific aim A, the angiogenic response of normal brain to PDT is tested and the effects of implantation of tumor in PDT induced angiogenic brain are analyzed. As a logical consequence of experiments performed in specific Aim A, we test the effects of combination treatment of U87 human glioma in the mouse brain using PDT and antiangiogenic agents in specific aim B. We expect that the combination treatment will significantly reduce the rate of tumor regrowth and thereby extend the life of animals compared to the individual treatments. The anti-angiogenic agents employed are antibodies against the vascular endothelial growth factor receptors (VEGFR1 and VEGFR2). If we are correct, that endogenous brain angiogenesis contributes to tumor regrowth, then our study has important implications for the treatment of brain tumor using most forms of anti tumor agents. Thus, the use of a combination anti-angiogenic and direct tumoricidal treatment may translate into improved therapeutic opportunity.