CLINICAL APPLICATIONS OF MODULATION OF DNA REPAIR PATHWAYS

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The clinical studies outlined in this specific aim target the manipulation of 06-methylguanine DNA methyltransferase (MGMT) in humans and are the result of extensive pre-clinical work demonstrating the efficacy of the approaches in animal models. One project proposes to increase the expression of MGMT in hematopoietic cells in an effort to diminish the cumulative myelosuppression commonly encountered with chloroethylnitrosoureas (CENUs). This project utilizes a recombinant retroviral vector extensively tested in murine studies and produced by the National Gene Vector Laboratory at Indiana University for human clinical trials. The clinical study builds on a current pilot study at Indiana University, designed by Dr. Regina Jakacki and supported in part by NCI funding, which utilities peripheral blood stem-progenitor cell infusions to decrease hematopoietic toxicities and allow schedule compression of an extensively used brain treatment protocol called "PCV" (procarbazine, CCNU, vincristine). The second project is designed to diminish expression of MGMT in tumor cells. Based on pre-clinical work by Dr. Leonard Erickson, MGMT can be effectively depleted from tumor cell lines by the sequential treatment with agents that produce the natural substrate for MGMT, 06-methylguanine, or act as a substrate for MGMT directly. One such agent, 06-benzylguanine (6-BG), is currently in phase I trials at other institutions. The specific aims of the study are: 1) To conduct a pilot study of dose-intensified procarbazine, CCNU, vincristine (PCV) for poor prognosis pediatric and adult brain tumor utilizing fibronectin-assisted, retroviral-mediated modification of CD34+ peripheral blood cells with 06-methylguanine DNA methyltransferase (MGMT). 2) To conduct a phase I trial to determine the toxicity of the combination of 06-benzylguanine and BCNU, and to examine the inhibition of MGMT activity in tumor biopsies in patients treated with this combination chemotherapy for relapsed B cell malignancies.