Jaeckle K A, Eyre H J, Townsend J J, Schulman S, Knudson H M, Belanich M, Yarosh D B, Bearman S I, Giroux D J, Schold S C
The University of Texas M.D. Anderson Cancer Center, Houston, USA.
J Clin Oncol. 1998 Oct;16(10):3310-5. doi: 10.1200/JCO.1998.16.10.3310.
Prior studies show that increased levels of the DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT), also referred to as O6-alkylguanine-DNA alkyltransferase (AGT) correlate with the resistance of glioma cell lines to nitrosoureas. The observed nitrosourea sensitivity of MGMT-deficient lines (methyl excision repair negative [MER-]) and those repair-proficient lines pretreated with MGMT-specific inhibitors (eg, O6 benzylguanine) has raised the possibility that tumor MGMT levels may be an important predictor of survival in patients with gliomas.
We correlated the MGMT level in malignant astrocytoma tissues, obtained from patients treated with radiotherapy and bis-chloroethylnitrosourea (BCNU) on a prior prospective trial (Southwest Oncology Group [SWOG] 8737), with overall and failure-free survival.
Of 64 assessable patients with malignant astrocytoma (63% glioblastoma, 37% anaplastic astrocytoma), 64% had high (> 60,000 molecules/nucleus) MGMT levels. The overall median survival for patients with high versus low MGMT levels was 8 and 29 months, respectively (P=.0002), and median failure-free survival 3 and 6 months, respectively (P=.008). Subset analysis by histology (high v low MGMT levels) for anaplastic astrocytoma was 14 versus 62 months (n=24) and for glioblastoma was 7 versus 12 months (n=40). The overall hazards ratio (risk for death) for high versus low MGMT levels was 3.41; in young patients, the hazards ratio was higher (age 18 to 40 years, 4.19; age 41 to 60 years, 3.08) but became equal by MGMT level at age older than 60 years (1.11). Multivariate analysis showed that MGMT was independent of other known prognostic factors (age, performance status, histology).
The MGMT level in tumor tissue specimens may be a predictive marker of survival in patients with malignant astrocytoma that is independent of other previously described prognostic variables.
先前的研究表明，DNA修复蛋白O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT），也称为O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）水平的升高与胶质瘤细胞系对亚硝基脲的耐药性相关。MGMT缺陷型细胞系（甲基切除修复阴性[MER-]）以及用MGMT特异性抑制剂（如O6-苄基鸟嘌呤）预处理的修复功能正常的细胞系对亚硝基脲的敏感性，提示肿瘤MGMT水平可能是胶质瘤患者生存的重要预测指标。
我们将恶性星形细胞瘤组织中的MGMT水平与总生存期和无进展生存期进行关联分析。这些组织取自一项先前的前瞻性试验（西南肿瘤协作组[SWOG]8737）中接受放疗和双氯乙基亚硝基脲（BCNU）治疗的患者。
在64例可评估的恶性星形细胞瘤患者中（63%为胶质母细胞瘤，37%为间变性星形细胞瘤），64%的患者MGMT水平较高（>60,000分子/细胞核）。MGMT水平高与低的患者的总中位生存期分别为8个月和29个月（P = 0.0002），无进展中位生存期分别为3个月和6个月（P = 0.008）。间变性星形细胞瘤按组织学进行的亚组分析（MGMT水平高与低）结果为14个月与62个月（n = 24），胶质母细胞瘤为7个月与12个月（n = 40）。MGMT水平高与低的患者的总风险比（死亡风险）为3.41；在年轻患者中，风险比更高（18至40岁，4.19；41至60岁，3.08），但在60岁以上患者中按MGMT水平划分风险比变得相同（1.11）。多因素分析显示，MGMT独立于其他已知的预后因素（年龄、体能状态、组织学）。
肿瘤组织标本中的MGMT水平可能是恶性星形细胞瘤患者生存的预测标志物，且独立于其他先前描述的预后变量。
