Does NO mediate clinical anti-VEGF vascular effects

描述（由申请人提供）：抗VEGF疗法是治疗和预防人类癌症的有前景的方法，但迄今为止仅报道了适度的临床活性。抗VEGF化合物的最佳剂量将是使临床功效最大化同时使毒性最小化的一个关键。最近出现了几种抗VEGF类相关毒性，包括高血压、蛋白尿、血栓形成和出血。除非了解抗VEGF机制，否则这些副作用的治疗可能无效，甚至可能干扰抗肿瘤作用。越来越多的证据表明，除了NO在调节血管张力和许多其他内皮功能中的已知作用外，一氧化氮（NO）还可作为VEGF效应的介体。因此，一氧化氮机制也可能直接或间接通过其他共同和反调节途径介导抗VEGF治疗的疗效和毒性。我们建议使用几种新的方法和抗VEGF治疗的独特临床环境来评估抗VEGF治疗对几种已知的VEGF/NO依赖性过程的临床效果。这些包括调节血压、内皮细胞血管反应性、伤口血管生成和血小板功能。我们还将确定这些影响是否介导的一氧化氮通过测量血浆和尿液中的亚硝酸盐/硝酸盐和呼出的NO。我们将采用低亚硝酸盐/硝酸盐饮食和舌下硝酸甘油的管理，以提高这些方法的灵敏度和特异性。肱动脉反应性将用于评估NO依赖性血管反应性。一种新的伤口血管生成模型将允许抗血管生成作用与组织VEGF/VEGFR-2磷酸化和一氧化氮合酶的变化的临床相关性。还将以探索性方式评价其他NO介导的事件。由于贝伐珠单抗是临床开发中沿着的抗VEGF化合物，因此该提案将重点关注该化合物。将在抗VEGF治疗的第一个月之前/之后进行密集的生物标志物评价。然而，为了获得潜在的临床获益，将允许患者接受医生认为适当的持续抗VEGF治疗。

DESCRIPTION (provided by applicant): Anti-VEGF therapy is a promising approach to the treatment and prevention of human cancers, but thus far only modest clinical activity has been reported. Optimal dosing of anti-VEGF compounds will be one key to maximizing clinical efficacy while minimizing toxicity. Recently several anti-VEGF class related toxicities have emerged, including hypertension, proteinuria, thrombosis, and bleeding. Unless anti-VEGF mechanisms are understood, treatments for these side effects may be inefficient or may even interfere with anti-tumor effects. Accumulating evidence points to a role for nitric oxide (NO) as a mediator of VEGF effects in addition to NO's known role in the regulation of vascular tone and many other endothelial functions. Thus, nitric oxide mechanisms may also mediate the efficacy and toxicity of anti-VEGF therapy either directly or indirectly via other co- and counter-regulatory pathways. We propose to use several novel approaches and the unique clinical setting of anti-VEGF therapy to evaluate the clinical effects of anti-VEGF treatment on several known VEGF/NO dependent processes. These include regulation of blood pressure, endothelial cell vasoreactivity, wound angiogenesis, and platelet function. We will also determine if these effects are mediated by nitric oxide by measuring plasma and urine nitrite/nitrate and exhaled NO. We will employ low nitrite/nitrate diets and administration of sublingual nitroglycerin to improve the sensitivity and specificity of these approaches. Brachial reactivity will be used to assess NO dependent vasoreactivity. A novel wound angiogenesis model will allow clinical correlation of anti-angiogenic effects with changes in tissue VEGF/VEGFR-2 phosphorylation, and nitric oxide synthase. Other NO mediated events will also be evaluated in an exploratory fashion. Since bevacizumab is the anti-VEGF compound furthest along in clinical development, the proposal will focus on this compound. Intense biomarker evaluations will be performed pre/post the first month of anti-VEGF treatment. However, to allow for potential clinical benefit, patients will be permitted to receive ongoing anti-VEGF therapy as deemed appropriate by their physician.