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.
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