Schilsky R L, Dolan M E, Bertucci D, Ewesuedo R B, Vogelzang N J, Mani S, Wilson L R, Ratain M J
Department of Medicine, Cancer Research Center and Committee on Clinical Pharmacology, University of Chicago, Illinois 60637, USA.
Clin Cancer Res. 2000 Aug;6(8):3025-31.
O6-benzylguanine (BG) is a potent inactivator of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) that enhances sensitivity to nitrosoureas in tumor cell lines and tumor-bearing animals. The major objectives of this study were to define the optimal modulatory dose and associated toxicities of benzylguanine administered alone and in combination with carmustine; to define the maximally tolerated dose and associated toxicities of carmustine administered with benzylguanine and to describe the pharmacokinetics of BG in humans and its effects on AGT depletion and recovery in peripheral blood mononuclear cells. Patients with histologically confirmed advanced solid tumors or lymphoma that had failed to respond to standard therapy or for which no standard therapy was available were eligible to participate in this study. Patients initially received BG as a 1-h i.v. infusion without carmustine. After a 14-day washout (ie., without therapy) period, patients received BG as a 1-h i.v. infusion followed, 1 h later, by a 15-min i.v. infusion of carmustine. Cycles of chemotherapy were repeated every 6 weeks. Cohorts of patients received BG doses ranging from 10 to 120 mg/m2 and carmustine doses ranging from 13 to 50 mg/m2. Plasma and urine samples were collected and analyzed for BG, and O6-benzyl-8-oxoguanine concentrations and AGT activity was determined in peripheral blood mononuclear cells. There was no toxicity attributable to BG alone at any dose tested. Bone marrow suppression was the primary and dose-limiting toxicity of BG combined with carmustine and was cumulative in some patients. The neutrophil nadir occurred at a median of day 27, with complete recovery in most patients by day 43. Nonhematological toxicity included fatigue, anorexia, increased bilirubin, and transaminase elevation. Recommended doses for Phase II testing are 120 mg/m2 BG given with carmustine at 40 mg/m2. BG rapidly disappeared from plasma and was converted to a major metabolite, O6-benzyl-8-oxoguanine, which has a 2.4-fold higher maximal concentration and 20-fold higher area under the concentration versus time curve than BG. AGT activity in peripheral blood mononuclear cells was rapidly and completely suppressed at all of the BG doses. The rate of AGT regeneration was more rapid for patients treated with the lowest dose of BG but was similar for BG doses ranging from 20-120 mg/m2. In conclusion, coadministration of BG and carmustine is feasible in cancer patients, but the maximal dose of carmustine that can be safely administered with BG is approximately one-third of the standard clinical dose. Bone marrow suppression, which may be cumulative, is the dose-limiting toxicity of the combination. Prolonged AGT suppression is likely attributable primarily to the effect of O6-benzyl-8-oxoguanine.
O6-苄基鸟嘌呤（BG）是一种有效的DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）灭活剂，可增强肿瘤细胞系和荷瘤动物对亚硝基脲的敏感性。本研究的主要目的是确定单独使用及与卡莫司汀联合使用时苄基鸟嘌呤的最佳调节剂量和相关毒性；确定与苄基鸟嘌呤联合使用时卡莫司汀的最大耐受剂量和相关毒性，并描述BG在人体内的药代动力学及其对外周血单核细胞中AGT耗竭和恢复的影响。经组织学证实的晚期实体瘤或淋巴瘤患者，若对标准治疗无反应或无标准治疗方案可用，则有资格参加本研究。患者最初接受1小时静脉输注BG，不联合卡莫司汀。经过14天的洗脱期（即不进行治疗）后，患者接受1小时静脉输注BG，1小时后再接受15分钟静脉输注卡莫司汀。化疗周期每6周重复一次。不同组患者接受的BG剂量范围为10至120mg/m²，卡莫司汀剂量范围为13至50mg/m²。采集血浆和尿液样本分析BG，并测定外周血单核细胞中的O6-苄基-8-氧代鸟嘌呤浓度和AGT活性。在任何测试剂量下，单独使用BG均无毒性。骨髓抑制是BG与卡莫司汀联合使用时的主要剂量限制性毒性，在一些患者中具有累积性。中性粒细胞最低点出现在第27天左右，大多数患者在第43天完全恢复。非血液学毒性包括疲劳、厌食、胆红素升高和转氨酶升高。II期试验的推荐剂量为120mg/m² BG与40mg/m²卡莫司汀联合使用。BG迅速从血浆中消失，并转化为主要代谢产物O6-苄基-8-氧代鸟嘌呤，其最大浓度比BG高2.4倍，浓度-时间曲线下面积比BG高20倍。在所有BG剂量下，外周血单核细胞中的AGT活性均迅速且完全受到抑制。接受最低剂量BG治疗的患者AGT再生速度更快，但BG剂量在20 - 120mg/m²范围内时再生速度相似。总之，BG与卡莫司汀联合给药在癌症患者中是可行的，但与BG联合安全给药时卡莫司汀的最大剂量约为标准临床剂量的三分之一。骨髓抑制可能具有累积性，是联合用药的剂量限制性毒性。AGT的长期抑制可能主要归因于O6-苄基-8-氧代鸟嘌呤的作用。
