Nitrosoureas are effective anti-tumor agents, especially in brain cancer. However, tumors are often resistant due to activity of the human DNA repair enzyme O6-methylguanine-DNA methyltransferase (06MT). The outcome of chemotherapy may e 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 human O6MT gene. The Phase I research proposes to 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 DNA probe hybridization assay will be developed, and compared with results from the enzyme activity assay for O6MT. A second objective is to compare the O6MT levels of tumor samples with patient response. Several parameters of patient response will be collected, including CAT scan, time to relapse and six-month survival. The range of O6MT levels in initially presented and failed treatment tumors will also be compared to determine if there is any difference. This will establish the usefulness of these assays in a clinical trial to predict drug-resistance and patient response to treatment.
