Does NO mediate clinical anti-VEGF vascular effects

描述(申请人提供)：抗血管内皮生长因子疗法是一种很有前途的治疗和预防人类癌症的方法，但到目前为止，只有少量的临床活性被报道。抗血管内皮生长因子化合物的最佳剂量将是在最大限度提高临床疗效的同时将毒性降至最低的关键之一。最近出现了一些与抗血管内皮生长因子类药物相关的毒性反应，包括高血压、蛋白尿、血栓形成和出血。除非了解抗血管内皮生长因子的机制，否则针对这些副作用的治疗可能是无效的，甚至可能干扰抗肿瘤作用。越来越多的证据表明，除了一氧化氮(NO)在调节血管张力和许多其他内皮功能方面的已知作用外，一氧化氮(NO)还作为血管内皮生长因子(VEGF)的中介作用。因此，一氧化氮机制也可能直接或间接地通过其他共调节和反调节途径介导抗血管内皮生长因子治疗的疗效和毒性。我们建议使用几种新的方法和独特的抗血管内皮生长因子治疗的临床环境来评估抗血管内皮生长因子治疗对几个已知的血管内皮生长因子/一氧化氮依赖过程的临床效果。这些包括对血压、内皮细胞血管反应性、伤口血管生成和血小板功能的调节。我们还将通过测量血浆和尿液中的亚硝酸盐/硝酸盐和呼出的NO来确定这些影响是否由一氧化氮介导。我们将采用低亚硝酸盐/硝酸盐饮食和舌下含服硝酸甘油来提高这些方法的敏感性和特异性。臂部反应性将被用来评估非依赖性血管反应性。一种新的创面血管生成模型将允许临床将抗血管生成效应与组织VEGF/VEGFR-2磷酸化和一氧化氮合酶的变化联系起来。其他没有调解的事件也将以探索性的方式进行评估。由于贝伐单抗是临床开发最深入的抗血管内皮生长因子化合物，该提案将重点放在该化合物上。在抗血管内皮生长因子治疗的第一个月之前/之后，将进行密集的生物标记物评估。然而，考虑到潜在的临床益处，患者将被允许接受医生认为合适的持续的抗血管内皮生长因子治疗。

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.