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

本研究的目的是测试两种抗癌药物O 6苄基鸟嘌呤和BCNU的组合，并确定抗癌活性的程度是否可以比单独使用BCNU得到改善，并确定O 6 BG的有效剂量和可以与O 6 BG一起安全给药的BCNU剂量。 迄今为止，31例患者接受了10 mg/m2- 120 mg/m2的BG剂量治疗。 在120 mg/m2的当前剂量下，已经进行了两次可评价的活检，并且没有检测到06-烷基鸟嘌呤DNA烷基转移酶（AGT）活性。 120 mg/m2剂量似乎代表消耗BG的AGT活性（BMDT）所需的剂量。我们研究中的一个重要发现是外周血单核细胞和肿瘤组织中AGT活性之间的相关性很差。 基线时PBMC中的AGT与肿瘤组织AGT无关。 在输注开始的15分钟内观察到PBMC中AGT的消耗，并且在2和6小时之间具有最低点。 AGT消耗维持24小时，第7天部分恢复，15天后恢复至基线。 PBMC AGT的总消耗发生在比肿瘤组织AGT更低剂量的BG下。

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.