GASTROINTESTINAL MOTOR EFFECTS OF IONIZING RADIATION

描述：（改编自研究者摘要）放射治疗是一种 治疗癌症的主要方式。 然而，由于应用程序和 这种治疗的疗效增加了，对正常的关注也增加了。 组织毒性 对于腹部和盆腔肿瘤的治疗， 肠耐受性通常是主要的限制因素。 研究报告 申请人的实验室和其他实验室已经证明了 小肠和结肠运动活动， 亚致死剂量的电离辐射 其中许多变化直接 与接受放射治疗的患者的症状相关， 导致呕吐胃肠道痉挛和腹泻 申请人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，重点放在负责 他们观察到的变化。 本研究的主要目的 建议1）探讨中枢和外周神经激肽1的作用 受体在辐射引起的收缩变化中，2） 了解小肠与小肠之间的协调机制， 和结肠收缩诱导的辐射和3），以确定的作用， 放射线中假定的抑制性神经递质一氧化氮 诱发收缩。 在犬模型中，将使用应变仪记录收缩。 将使用无菌手术技术将其植入动物体内。 神经激肽1受体拮抗剂或一氧化氮合酶抑制剂 将通过静脉内、脑室内或 在清醒和神经系统完整的患者中使用闭合动脉内技术 动物 将在啮齿动物模型中进行更详细的研究 结果与临床相关的运动模型相关 变化 最终目的是阐明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， 申请人将能够提出适当的药理学试剂来阻断 这些胃肠道的影响，并提高人体对辐射的耐受性 exposure.

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.