GASTROINTESTINAL MOTOR EFFECTS OF IONIZING RADIATION

描述：(改编自研究人员摘要)放射治疗是一种 是治疗癌症的主要方法。但是，由于应用程序和 这种治疗的疗效提高了，所以对正常的关注也增加了 组织毒性。用于治疗腹部和盆腔肿瘤， 肠道耐受性往往是一个主要的限制因素。研究来自于 申请者的实验室和其他实验室展示了戏剧性的变化 分次或单一后的小肠和结肠动力活动 亚致死剂量的电离辐射。这些变化中的许多都直接 与接受放射治疗的患者有关的症状 导致呕吐、胃肠痉挛和爆发性腹泻。 申请者将收缩变化的改善与 改善患者耐受性的药物干预。他们现在 建议继续努力，重点是负责 他们观察到的变化。这项研究的主要目标是 建议1)探讨中枢和外周神经激肽1的作用 辐射引起的收缩变化中的受体，2)到 了解小肠之间协调的机制 和由辐射引起的结肠收缩，以及3)确定 辐射中假定的抑制性神经递质--一氧化氮 诱发宫缩。 在犬类模型中，将使用应变仪进行收缩记录。 他们将使用无菌外科技术被植入动物体内。 神经激肽1受体拮抗剂或一氧化氮合酶抑制剂 将通过静脉、脑室或 在意识和神经功能完好的情况下使用动脉闭合技术 动物。将在啮齿动物模型中进行更详细的调查 这些结果与临床相关的运动模型相关联 改变。 最终目的是描述产生异常运动的机制。 在人类放射治疗过程中的模式。有了这样的理解， 申请者将能够提出适当的药理药物来阻止 这些胃肠道效应和提高人类对辐射的耐受性 曝光。

DESCRIPTION: (Adapted from investigator's abstract) Radiation therapy is a major modality in the treatment of cancer. However, as the application and efficacy of this treatment has increased, so has the concern for normal tissue toxicity. For the treatment of abdominal and pelvic tumors, intestinal tolerance is often a major limiting factor. Studies from the applicants' lab and other laboratories have demonstrated dramatic changes in small intestinal and colonic motor activity following fractionated or single sub-lethal doses of ionizing radiation. Many of these changes have direct symptomatic relevance to patients receiving radiation therapy and are responsible for emesis, gastrointestinal cramping and explosive diarrhea. The applicants have correlated improvements in the contractile changes with pharmacologic interventions which improve patient tolerance. They now propose to continue the efforts, focusing on the mechanisms responsible for the changes they have observed. The primary objectives of this research proposal are 1) to explore the role of central and peripheral neurokinin 1 receptors in the contractile changes produced by irradiation, 2) to understand the mechanisms of the coordination between the small intestinal and colonic contractions induced by irradiation and 3) to define the role of the putative inhibitory neurotransmitter, nitric oxide, in the radiation induced contractions. In a canine model, contractile recordings will be made using strain gauges. They will be implanted in the animals using sterile surgical techniques. Antagonists of neurokinin 1 receptor or nitric oxide synthase inhibitors will be administered either intravenously, intracerebroventricularly or using close intraarterial techniques in conscious and neurologically intact animals. More detailed investigations will be performed in a rodent model and the results correlated with the clinically relevant model of motility changes. The ultimate aim is to delineate the mechanisms that produce abnormal motor patterns during radiation therapy in humans. With this understanding, the applicants will be able to propose appropriate pharmacologic agents to block these gastrointestinal effects and improve human tolerance to radiation exposure.