) The objective of this proposal is to develop new, laboratory-based chemotherapeutic treatment strategies for application in the phase I setting. These phase I studies will lead not only to the assignment of a maximum tolerated dose and to an understanding of the spectrum of normal tissue toxicity for specific antineoplastic agents that target novel molecular pathways, but will also provide a mechanistic evaluation of the effects of the agents on critical tumor cell functions. This objective will be pursued by a group of molecular pharmacologists and clinical scientists from two NCI-designated Cancer Centers and a large University Hospital who will use the extensive laboratory and patient resources of the City of Hope National Medical Center (COH), the Kenneth Norris, Jr. Comprehensive Cancer Center at the University of Southern California (USC), and the University of California, Davis Cancer Center to perform phase I molecular pharmacodynamic studies that focus on: 1) novel compounds which significantly modify patterns of DNA methylation or directly inhibit the activity of DNA methyltransferase as a unique antineoplastic activity; 2) new agents which produce critical alterations in cell cycle checkpoint control or cell cycle progression as their mechanism of action; 3) the role of antineoplastic drug concentration (rather than dose) in the efficacy and toxicity of dose-intensive chemotherapy, as well as the effects of abnormal organ function on the pharmacokinetics and pharmacodynamics of new antineoplastic agents available from the Cancer Therapy Evaluation Program of the NCI; and 4) the identification of new antineoplastic agents available from the Cancer Therapy Evaluation Program of the NCI; and 4) the identification of new molecular correlates of therapeutic activity and drug resistance, including new markers of DNA damage, repair, and methylation, for compounds with novel mechanisms of action, as well as for the taxane, platinum, antimetabolite, and topoisomerase I drug classes. Based on a significant record of patient accrual, as well as substantive clinical, biostatistical, and laboratory interactions during the past three years which have provided the rationale for a novel set of proposed phase I trials, the investigators at COH, USC, and UCD are well suited to rapidly complete pharmacologically-driven phase I trials of anticancer agents targeting critical new intracellular pathways.
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