) This research proposes to develop new knowledge relevant to the treatment of cancer by conducting phase I studies of new anticancer drugs and pharmacologic modulatory regimens which attempt to enhance the therapeutic efficacy of new drugs. Concurrent with the clinical studies, the research will evaluate the distribution and metabolism of the study drugs and examine their biological effects at the clinical biochemical and molecular level.
The Specific Aims of this proposal will be: 1)Putative Cytodifferentiation Agents: The institution has a long-standing interest in differentiation agents including studies of HMBA, all trans-retinoic acid, 9-cis retinoic acid, RXR specific ligands and phenylbutyrate (supported under other mechanisms). Studies under this agreement are planned for new bryostatin analogs (UCN-01) and other differentiation inducing agents currently under development at CTEP. 2)Signal Transduction Targets: MSKCC laboratories have national leadership roles in the evaluation of ras inhibitors, ceramide mediated signaling and the interaction between factors and cytotoxic chemotherapy. Inhibition of protein kinase C will be a target of particular interest. Trials of these agents, alone and in combination with cisplatin, paclitaxel and mitomycin C are planned. 3)Reversal of Drug Resistance: The mechanisms of drug resistance continue to be a major area of interest for the pharmacology group at MSKCC. Combination studies of established agents and agents with novel mechanisms which appears to interfere with the acquisition and maintenance of drug resistance are planned. One such combination would be cisplatin and flavopiridol. 4)Phase I Testing of Disease Specific Therapies: One of the strengths of MSKCC is its large patient population. Through this cooperative agreement, we will look for particularly interesting agents which require early targeting to specific cancer types. Our high patient volume will allow us to rapidly complete such studies. A good example of one such trial is the proposed study of vaccine therapy for prostate cancer. T h e studies to be performed during the funding period will include pharmacokinetric studies, studies of adaptive dosing and pharmacodynamic studies of new agents or combinations. Laboratory correlates, based on tumor biopsies or surrogate tissues will also be performed as appropriate. Quality of life and cost of therapy vs alternative therapy will be prospectively collected for all studies.
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