The purpose of this project is to continue to optimize the use of cytotoxic agents in BMT. Our efforts will be based on increasing knowledge of the pharmacokinetics and pharmacodynamics of the agents used and of the drug responsiveness determinants of the target tumors. In the previous period of funding, we have demonstrative that the incidence of veno-occlusive disease of the liver and mucositis in BMT patients receiving busulfan can be reduced without compromising the therapeutic effect by pharmacokinetics monitoring and dose adjustment of the busulfan. We have also demonstrated that the 4-HC sensitivity of the residual leukemia and lymphoma cells in patients undergoing Bu/Cy autologous BMT is a very significant predictor of the long term survival of the patients. We shall continue our studies of the pharmacokinetics of busulfan, focusing on the use of a new intravenous preparation, to produce more consistent plasma levels of the agent. We shall also continue our studies of the pharmacokinetics of cyclophosphamide and its primary active metabolite, 4-hydroperoxycyclophosphamide, and of etoposide, seeking correlations between the pharmacokinetics of these agents and clinical outcome and ascertaining the potential for dose modulation of these drugs. We shall also continue our studies of the sensitivity of tumor cells from BMT patients to the above agents, and the elucidation and measurements of the cellular determinants of such sensitivity. The tumor cells will be obtained as the residual tumor cells from the harvested marrow of autologous patients, from relapsed patients, and, when possible from patients prior to remission induction and BMT.