Phase I clinical and pharmacological study of O6-benzylguanine followed by carmustine in patients with advanced cancer.
Phase I clinical and pharmacological study of O6-benzylguanine followed by carmustine in patients with advanced cancer.
复制标题
DOI：
--
复制
发表时间：
2000-08
期刊：
影响因子：
--
通讯作者：
R. Schilsky;M. Dolan;D. Bertucci;R. Ewesuedo;N. Vogelzang;S. Mani;L. R. Wilson;M. Ratain
中科院分区：
文献类型：
--
作者：
R. Schilsky;M. Dolan;D. Bertucci;R. Ewesuedo;N. Vogelzang;S. Mani;L. R. Wilson;M. Ratain
o6 -苄基鸟嘌呤（BG）是DNA修复蛋白o6 -烷基鸟嘌呤-DNA烷基转移酶（AGT）的有效失活剂，可增强肿瘤细胞系和荷瘤动物对亚硝基源的敏感性。本研究的主要目的是确定苯鸟嘌呤单独使用和与卡莫司汀联合使用的最佳调节剂量和相关毒性；定义卡莫汀与苄鸟嘌呤联合使用的最大耐受剂量和相关毒性，描述BG在人体内的药代动力学及其对外周血单个核细胞中AGT消耗和恢复的影响。组织学证实的晚期实体瘤或淋巴瘤患者对标准治疗无效或无标准治疗可用，符合参加本研究的资格。患者最初接受不含卡莫司汀的1小时静脉输注BG。经过14天的洗脱期(即：（无治疗）期间，患者接受BG 1小时静脉输注，1小时后，静脉输注卡莫司汀15分钟。化疗周期每6周重复一次。患者队列接受BG剂量范围为10至120mg /m2，卡莫司汀剂量范围为13至50mg /m2。收集血浆和尿液样本，分析BG，测定外周血单个核细胞中o6 -苄基-8-氧鸟嘌呤浓度和AGT活性。在任何剂量的测试中，没有单独归因于BG的毒性。骨髓抑制是BG联合卡莫司汀的主要毒性和剂量限制性毒性，在一些患者中是累积性的。中性粒细胞最低点发生在27天，大多数患者在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120 mg/m2 BG和40 mg/m2的卡莫司汀。BG迅速从血浆中消失，转化为主要代谢物o6 -苄基-8-氧鸟嘌呤，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。在所有的BG剂量下，外周血单个核细胞的AGT活性都被迅速而完全地抑制。使用最低剂量BG治疗的患者的AGT再生速度更快，但在20-120 mg/m2的BG剂量范围内，AGT再生速度相似。综上所述，在癌症患者中，BG和卡莫司汀联合给药是可行的，但与BG一起安全给药的卡莫司汀的最大剂量约为临床标准剂量的三分之一。骨髓抑制，可能是累积的，是剂量限制的毒性组合。延长AGT抑制可能主要归因于o6 -苄基-8-氧鸟嘌呤的作用。
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.