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

本研究的目的是测试O6Benzylguanine和BCNU两种抗癌药物的联合使用，确定是否能比单独使用BCNU提高抗癌活性的程度，并确定O6BG的有效剂量和BCNU与O6BG可以安全给药的剂量。迄今为止，31名患者接受了10mg/m2-120mg/m2剂量的BG治疗。在当前剂量为120 mg/m2时，进行了两次可评估的活组织检查，未检测到06-烷基鸟嘌呤DNA烷基转移酶（AGT）活性。120 mg/m2的剂量似乎代表了消耗BG的AGT活性（BMDT）所需的剂量。我们研究的一个重要发现是外周血单核细胞（PBMC）中AGT活性与肿瘤组织的相关性较差。PBMC基线AGT与肿瘤组织AGT无相关性。在开始输注后15分钟内观察到PBMC中AGT的消耗，并在2至6小时之间达到最低点。AGT耗竭维持24小时，7天后部分恢复，15天后恢复到基线水平。与肿瘤组织AGT相比，BG剂量较低时，PBMC AGT的总耗损发生。

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.