MEASUREMENT OF O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE IN HUMAN TUMORS

NITROSOUREAS ARE EFFECTIVE ANTITUMOR AGENTS, ESPECIALLY IN BRAIN CANCER. HOWEVER, TUMORS ARE OFTEN RESISTANT DUE TO ACTIVITY OF THE HUMAN DNA REPAIR ENZYME, O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (O6MT). THE OUTCOME OF CHEMOTHERAPY MAY BE PREDICTED BY MEASURING THE LEVELS OF O6MT IN SINGLE CELLS FROM TUMOR BIOPSIES, AND A MORE RATIONAL TREATMENT REGIME MAY BE DESIGNED. THIS APPROACH IS NOW FEASIBLE BECAUSE OF THE CLONING OF THE HUMANO6MT GENE. THE PHASE I RESEARCH WILL USE POLYCLONAL ANTIBODIES AND DNA PROBES TO MEASURE O6MT LEVELS IN HUMAN TUMOR SAMPLES TAKEN AT INITIAL BIOPSY AND AT SECOND-LOOK SURGERY. THE IMMUNOHISTOCHEMICAL AND IN SITU HYBRIDIZATION ASSAY WILL BE DEVELOPED, AND TEST RESULTS WILL BE CORRELATED WITH PATIENT OUTCOME. THIS WILL ESTABLISH THE USEFULNESS OF THESE ASSAYS IN A CLINICAL TRIAL TO PREDICT DRUG RESISTANCE AND PATIENT RESPONSE TO TREATMENT.