Friedman H S, Kokkinakis D M, Pluda J, Friedman A H, Cokgor I, Haglund M M, Ashley D M, Rich J, Dolan M E, Pegg A E, Moschel R C, McLendon R E, Kerby T, Herndon J E, Bigner D D, Schold S C
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
J Clin Oncol. 1998 Nov;16(11):3570-5. doi: 10.1200/JCO.1998.16.11.3570.
The major mechanism of resistance to alkylnitrosourea therapy is the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which removes chlorethylation or methylation damage from the O6-position of guanine. O6-benzylguanine (O6-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.
Patients were to be treated 18 hours before craniotomy with intravenous doses that ranged between 40 and 100 mg/m2 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 O6-BG, with a target end point of > or = 11 of 13 patients with undetectable tumor AGT levels (< 10 fmol/mg protein).
Thirty patients with malignant gliomas were enrolled, with 11 of 11 patients treated at 100 mg/m2 O6-BG demonstrating tumor AGT levels less than 10 fmol/mg protein. No toxicity was noted in any patient treated.
These results indicate that 100 mg/m2 of O6-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/m2 dose of O6-BG will be used in combination with BCNU in another phase I trial designed to determine the maximal-tolerated dose of BCNU.
对烷基硝基脲疗法产生耐药性的主要机制是DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶（AGT），它可去除鸟嘌呤O6位上的氯乙基化或甲基化损伤。O6-苄基鸟嘌呤（O6-BG）是一种AGT底物，通过自杀性失活抑制AGT。我们进行了一项I期试验，以确定恶性胶质瘤患者术前使肿瘤AGT活性耗竭所需的剂量。
患者在开颅手术前18小时接受静脉注射治疗，剂量范围为40至100mg/m²，输注时间为1小时。切除的肿瘤在液氮中速冻，通过高压液相色谱（HPLC）分析AGT活性。以特定剂量的O6-BG治疗多达13名患者，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（<10fmol/mg蛋白质）。
30例恶性胶质瘤患者入组，11例接受100mg/m² O6-BG治疗的患者肿瘤AGT水平低于10fmol/mg蛋白质。所有接受治疗的患者均未出现毒性反应。
这些结果表明，100mg/m²的O6-BG可使治疗后至少18小时内肿瘤AGT水平维持在低于10fmol/mg蛋白质，在此时间间隔内，双（2-氯乙基）硝基脲（BCNU）诱导的氯乙基加合物可完全转化为链间交联。在另一项旨在确定BCNU最大耐受剂量的I期试验中，将使用100mg/m²剂量的O6-BG与BCNU联合使用。
