Development of Vascular Disrupting Agents

靶向肿瘤血管被证明是癌症治疗的有效方法。除了施用抗血管生成药物之外，补充策略是使用血管破坏剂来破坏肿瘤内皮细胞，其直接关闭肿瘤血管灌注。我们的初步研究表明，芪衍生物，芪5c，可以有效地抑制肿瘤血管灌注，而不损害正常器官灌注。然而，作为单一药剂使用的芪在异种移植模型中仅具有边际治疗功效。我们建议研究芪治疗后发生的肿瘤血管抑制和代偿性肿瘤机制的机制。具体目标1是研究二苯乙烯如何抑制肿瘤血流。各种成像方式，包括高频超声，荧光素酶成像，和使用氧血流传感器以及肿瘤血管密度的评估将用于研究二苯乙烯治疗后的肿瘤血流。具体目标2将调查我们初步研究中观察到的反弹现象。特别是，这项工作将集中在一氧化氮诱导的血管舒张的贡献。具体目标3将研究HIF-a和VEGF对芪5c的有效性的作用。我们将定量循环内皮祖细胞的水平，并使用小干扰RNA下调HIF-α和VEGF，以评估它们参与内皮祖细胞的动员和对芪5c治疗效果的影响。本研究的成功完成将有助于阐明一类新的血管阻断剂的作用机制和代偿反应，以促进其未来的临床应用。

Targeting tumor vessels is proving to be an effective approach in cancer therapy. In addition to the administration of anti-angiogenic drugs, a complementary strategy is to use vascular disrupting agents to damage tumor endothelial cells, which directly shuts down tumor vascular perfusion. Our preliminary studies show that the stilbene derivative, Stilbene 5c, can effectively suppress tumor vascular perfusion without compromising normal organ perfusion. However, stilbene used as a single agent has only marginal therapeutic efficacy in xenograft models. We propose to investigate the mechanism(s) of tumor vascular suppression and compensatory tumor mechanisms that occur after stilbene treatment. Specific aim 1 is to study how stilbene suppresses tumor blood flow. Various imaging modalities, including high frequency ultrasound, luciferase imaging, and the use of oxygen blood flow sensors as well as assessment of tumor vascular density will be used to investigate tumor blood flow after stilbene treatment. Specific aim 2 will investigate the rebound phenomenon observed in our preliminary studies. In particular, the work will focus on the contribution of nitric oxide-induced vasodilatation. Specific aim 3 will investigate the roles of HIF-a and VEGF on the effectiveness of stilbene 5c. We will quantify the levels of circulating endothelial progenitor cells and use small interfering RNA to down-regulate HIF-a and VEGF to assess their involvement in mobilization of endothelial progenitor cells and influence on therapeutic efficacy of stilbene 5c. Successful completion of this study will serve to elucidate the mechanisms of action and compensatory responses to a new class of vascular disrupting agents with the goal of facilitating their future clinical application.