09O6-BENZYLGUANINE AND BCNU--A BIOCHEMICAL MODULATION TRIAL

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The purposes of this study are to test a combination of two anticancer drugs, O6Benzylguanine and BCNU, and determine if the degree of anticancer activity can be improved over that of BCNU alone and to determine an effective dose of O6BG and the dose of BCNU that can be administered safely with O6BG. To date, 31 patients have been treated at doses of BG from 10mg/m2-120mg/m2. At the current dose of 120 mg/m2 two evaluable biopsies have been performed and no 06-alkylguanine DNA alkyltransferase (AGT) activity has been detected. The 120 mg/m2 dose appears to represent the dose required to deplete AGT activity (BMDT) of BG. An important finding in our study has been the poor correlation between AGT activity in Peripheral Blood Mononuclear Cells PBMC and tumor tissue. AGT in PBMC at baseline did not correlate with tumor tissue AGT. Depletion of AGT in PBMC was observed within 15 minutes of the commencement of the infusion, and had a nadir between 2 and 6 hours. AGT depletion was maintained for 24 hours, recovered partially at seven days and returned to baseline after 15 days. Total depletion of PBMC AGT occurred at lower doses of BG than tumor tissue AGT.