PATHOPHYSIOLOGY AND PREVENTION OF MULTIORGAN FAILURE

该项目的总体目标是改善 骨髓和外周血造血干细胞移植 发病率和消除死亡率由于肝脏，肾脏和 移植准备方案的肺毒性。 的 将采取的战略是首先确定 导致器官毒性，根据这些发现， 介入 因此，本项目的第一个目标是确定 涉及肝脏、肾脏和肺的急性毒性程度 a）与接触异常高水平的有毒代谢物有关 B）对低剂量环磷酰胺（CY）引起的宿主易感性 还原型谷胱甘肽的组织储存。 因此，CY的可变性 在一个大的患者群体中， 将测量相同剂量的CY并与观察到的CY进行比较。 毒性 同样，谷胱甘肽储存将在此确定， 人口 如果像我们预期的那样， 暴露于异常高水平的CY代谢物或低水平的 储存谷胱甘肽，我们的第二个目标将是研究方法， 避免暴露于有害水平的代谢物和/或 谷胱甘肽储存。 为了避免过度暴露， 基于醛脱氢酶-1预测异常CY代谢 将研究P450活性的活性或模式。 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， 我认为，通过上述方法，所有器官的损伤都可以避免 该项目的第三个具体目标是开发治疗方法， 其限制了初始损伤后的器官损伤，例如， 蛋白C输注预防静脉闭塞性疾病（VOD）， 醋酸奥曲肽预防VOD患者的液体潴留。 成功地实现我们的目标， 各种剂量强化化疗方案的结果。

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.