This proposal links preclinical laboratories at the U.T.M.D. Anderson Cancer Center with clinical studies that are tightly integrated with the laboratory programs. The hypothesis to be tested is that the development of anticancer drugs can be facilitated through integration of intermediate biochemical endpoints into phase I clinical trials. Achieving this goal is critical for the evaluation of the next generation of mechanistically and structurally novel drugs developed to modulate or inhibit specific molecular and biochemical targets. To expeditiously evaluate such agents requires effective cooperation between clinical and laboratory investigators. These lab components include analytical chemistry, clinical pharmacology and basic research laboratories capable of examining the interaction of the agent with specific cellular and molecular endpoints. In addition, some investigational agents will be evaluated best in special clinical settings such as in patients with leukemia or by using regional drug- administration approaches. These clinical situations present special challenges for drug development, but because of access to malignant cells they also present opportunities to incorporate unique pharmacologic, pharmacodynamic, and biochemical endpoints into the study of compounds developed in these settings. Finally, many rationally designed agents are extremely potent, thereby requiring development of highly sophisticated analytical methodologies to effectively measure the parent compound and metabolites in biologic systems. Based on these considerations our Specific Aims are: 1. To evaluate the clinical effects, pharmacokinetic parameters, and pharmacodynamic relationships of new agents selected on the basis of their novel structures and/or mechanisms of action. 2. To characterize the interaction(s) between the agent and its presumed molecular target(s) in accessible fluids and/or tissues (especially, where possible, in tumor tissue), and to relate this information to the toxicity and any anticancer activity observed during early clinical trials. 3. To evaluate the role of novel analytical techniques, especially the combination of HPLC with mass spectrometry to measure these agents and their metabolism in complex biologic systems. 4. To evaluate novel anticancer agents in two specific clinical settings selected to facilitate acquisition of tumor cells for laboratory investigations: a. acute leukemia; b. intraperitoneal administration to appropriate patients with solid tumors.
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