Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma
Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma
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DOI：
10.1200/jco.1998.16.11.3570
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发表时间：
1998-11-01
影响因子：
45.3
通讯作者：
Schold, SC
中科院分区：
文献类型：
--
作者：
Friedman, HS;Kokkinakis, DM;Schold, SC
用途：对烷基亚硝基脲治疗耐药的主要机制是DNA修复蛋白O-6-烷基鸟嘌呤-DNA烷基转移酶（AGT），其从鸟嘌呤的O-6-位置去除了甲基化或甲基化损伤。O-6-苄基鸟嘌呤（O-6-BG）是AGT的底物，通过自杀失活抑制AGT。我们进行了一项I期试验，以确定恶性胶质瘤患者肿瘤AGT活性耗竭所需的术前剂量。材料和方法：患者在开颅手术前18小时接受静脉注射，剂量范围为40 - 100 mg/m2，持续1小时。将切除的肿瘤在液氮中快速冷冻，并通过高压液相色谱法（HPLC）分析AGT活性。多达13名患者接受了特定剂量的O-6-BG治疗，目标终点是13名患者中有11名患者的肿瘤AGT水平检测不到结果：30例恶性胶质瘤患者入选; 11例接受100 mg/m2 O-6-BG治疗的患者中有11例显示肿瘤AGT水平低于10 fmol/mg蛋白。结论：100 mg/m2的O-6-BG可使肿瘤AGT水平在治疗后至少18小时内保持在10 fmol/mg蛋白以下，在此时间间隔内，BCNU诱导的氯乙基加合物完全转化为链间交联。在另一项I期试验中，100 mg/m2剂量的O-6-BG将与BCNU联合使用，该试验旨在确定BCNU的最大耐受剂量。(C)1998年，美国临床肿瘤学会。
Purpose: The major mechanism of resistance to alkylnitrosourea therapy is the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT), which removes chlorethylation or methylation damage from the O-6-position of guanine. O-6-benzylguanine (O-6-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial to define the presurgical dose required for depletion of tumor AGT activity in patients with malignant glioma.Material and Methods: patients were to be treated 18 hours before craniotomy with intravenous doses that ranged between 40 and 100 mg/m(2) given over 1 hour. Resected tumor was snap-frozen in liquid nitrogen and AGT activity analyzed by high-pressure liquid chromatography (HPLC). Up to 13 patients were treated at a specific dose of O-6-BG, with a target end point of greater than or equal to 11 of 13 patients with undetectable tumor AGT levels (< 10 fmol/mg protein).Results: Thirty patients with malignant gliomas were enrolled; with 11 of 11 patients treated at 100 mg/m(2) O-6-BG demonstrating tumor AGT levels less than 10 fmol/mg protein. No toxicity was noted in any patient treated.Conclusion: These results indicate that 100 mg/m(2) of O-6-BG can maintain tumor AGT levels less than 10 fmol/mg protein for at least 18 hours after treatment, a time interval in which bis(2-chloroethyl)nitrosourea (BCNU)-induced chloroethyl adducts are fully converted into interstrand cross-links. A 100-mg/m(2) dose of O-6-BG will be used in combination with BCNU in another phase I trial designed to determine the maximal-tolerated dose of BCNU. (C) 1998 by American Society of Clinical Oncology.