The objective of this proposal is to carry out clinical pharmacological investigations designed to improve chemotherapy of malignancy in two major ways. The first approach is to identify critical determinants of drug action in myeloproliferative and lymphoproliferative disorders and solid tumors with the ultimate purpose of designing tailored chemotherapy for the patient with cancer. These studies will be carried out by evaluating drug activation in tumor cells, retention of active metabolite within the cell, specific DNA damage as a result of exposure to the drug, levels of nucleotides and of activating and catabolizing enzymes, corticosteroid receptors and other biochemical pharmacological determinants of response and correlating these with sensitivity of the tumor cells in soft agar, cell kinetic parameters and pharmacokinetic parameters in vivo: all of these parameters would be correlated with clinical response. The second major approach will be the clinical testing and study of new drugs including their pharmacokinetics and metabolism and of drug combinations based on biochemical rationales including modulation of antimetabolite action by normal metabolites and other antimetabolites. A key aspect of the proposal is the close interaction with a biomathematics unit providing biostatistical and modeling inputs.