PATHOPHYSIOLOGY AND PREVENTION OF MULTIORGAN FAILURE

该项目的总体目标是提高术后的存活率 减少骨髓和外周血干细胞移植 肝、肾、肾疾病的发病率和消除死亡率 移植准备方案的肺部毒性。这个 将采取的战略是首先确定以下因素 会导致器官毒性，根据这些发现， 进行干预。因此，这个项目的第一个目标是确定 急性毒性涉及肝、肾和肺的程度 与a)接触异常高水平的有毒代谢物有关 环磷酰胺(CY)对宿主易感性的影响 储存还原型谷胱甘肽的组织。因此，CY的可变性 接受药物治疗的一大群患者中的代谢物暴露 将测量相同剂量的CY，并与观察到的CY进行比较 毒物。同样，谷胱甘肽商店将在这一点上确定 人口。如果，正如我们预期的那样，所看到的毒性程度与 暴露于异常高水平的CY代谢物或低水平CY代谢物 储存谷胱甘肽，我们的第二个目标将是研究 避免接触有害水平的代谢物和/或补充 谷胱甘肽商店。为了避免过度暴露，分析表明 基于乙醛脱氢酶-1的CY代谢异常预测 将研究P450的活性或活性模式。如果减少 谷胱甘肽储存与器官毒性有关，谷胱甘肽的研究 将进行补充。因为这可能是不现实的 认为所有的器官损伤都可以通过上述方法来避免 措施，这个项目的第三个具体目标是开发治疗方法 在最初的侮辱后限制器官损害，例如， 蛋白C输注预防静脉闭塞性疾病(VOD)和 奥曲肽用于预防VOD患者的液体滞留。 成功地实现我们的目标应该会改善结果 各种剂量密集的化疗方案。

The overall objective of this Project is to improve survival after marrow and peripheral blood stem cell transplantation by reducing morbidity and eliminating mortality due to the liver, renal and pulmonary toxicities of the transplant preparative regimen. The strategy which will be taken is to first identify the factors that contribute to organ toxicity and, based on these findings, to then intervene. Thus, the first aim of this project is to determine the extent to which acute toxicities involving the liver, kidneys and lungs are related a) to exposure to unusually high levels of toxic metabolites of cyclophosphamide (CY), and b) to host predisposition caused by low tissue stores of reduced glutathione. Thus, the variability of CY metabolite exposure among a large group of patients receiving identical doses of CY will be measured and compared with observed toxicities. Similarly, glutathione stores will be determined in this population. If, as we expect, the extent of toxicities seen are related to either exposure to unusually high levels of CY metabolites or low stores of glutathione, our second aim will be to study methods to avoid exposure to harmful levels of metabolites and/or replete glutathione stores. In order to avoid excess exposure, assays that predict unusual CY metabolism based on aldehyde dehydrogenase-1 activity or patterns of P450 activity will be studied. If reduced glutathione stores are related to organ toxicity, studies of glutathione supplementation will be undertaken. Because it may be unrealistic to think that all organ damage can be avoided through the above measures, the third specific aim of this project is to develop therapies which limit organ damage after the initial insult using, for example, protein C infusions to prevent venocclusive disease (VOD) and octreotide acetate to prevent fluid retention in patients with VOD. Success in the achievement of our aims should improve the outcome of various dose-intensive chemotherapy regimens.