Nagane M, Shibui S, Oyama H, Asai A, Kuchino Y, Nomura K
Department of Neurosurgery, National Cancer Center Hospital, Tokyo, Japan.
Surg Neurol. 1995 Nov;44(5):462-8; discussion 468-70. doi: 10.1016/0090-3019(95)00299-5.
Glioblastoma multiforme represents one of the most malignant forms of primary intracranial tumors, often intractable to multimodality of treatment including chemotherapy. The unsatisfactory results of chemotherapy are chiefly attributed to chemoresistance. Since various molecules that could confer drug resistance have been elucidated, screening of the amount of such molecules in the tumor cells could provide possibilities for predicting their chemoresistance beforehand and help select more effective drugs.
We present a 45-year-old woman with recurrent glioblastoma multiforme in the cerebellum and invading the brain stem, treated successfully by postoperative chemotherapy. In this patient, anticancer drugs were determined by measurements of mRNA expression of chemoresistance-related genes, such as O6-methylguanine-DNA methyltransferase (MGMT), mdr1, glutathione S-transferase (GST)-pi, and metallothionein (MT) in the resected tumor.
Northern blot analysis demonstrated the moderate mRNA level of MGMT, a major molecule causing ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride) resistance. On the other hand, expression levels of mdr1 which codes the P-glycoprotein responsible for multidrug resistance, and GST-pi, a detoxification enzyme, were low. Transcript of MT, another thiol containing molecule for cellular detoxification possibly associated with cisdiamminedichloroplatinum(II) (CDDP) resistance, was only faintly detectable. Postoperatively, the patient was treated initially with intravenous administration of ACNU and etoposide (VP16), resulting in a minor response of tumor regression. For maintenance therapy, we changed ACNU to CDDP according to the findings of the Northern blot analysis. Consequently, the residual tumor showed a marked response and almost disappeared after two courses of systemic chemotherapy with CDDP and VP16.
The successful tumor regression in this case suggests that Northern blot analysis on expression of these chemoresistance-related genes in tumor tissues could provide beneficial information for determination of optimal anticancer agents to improve the efficacy of chemotherapy.
多形性胶质母细胞瘤是原发性颅内肿瘤中最恶性的肿瘤之一，通常对包括化疗在内的多模式治疗难以治愈。化疗效果不理想主要归因于化疗耐药性。由于已经阐明了各种可赋予耐药性的分子，因此筛选肿瘤细胞中此类分子的数量可为预先预测其化疗耐药性提供可能性，并有助于选择更有效的药物。
我们报告一名45岁复发性小脑多形性胶质母细胞瘤并侵犯脑干的女性患者，经术后化疗成功治疗。在该患者中，通过测量切除肿瘤中与化疗耐药相关基因的mRNA表达来确定抗癌药物，这些基因包括O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）、mdr1、谷胱甘肽S-转移酶（GST）-π和金属硫蛋白（MT）。
Northern印迹分析显示MGMT的mRNA水平中等，MGMT是导致ACNU（1-（4-氨基-2-甲基-5-嘧啶基）甲基-3-（2-氯乙基）-3-亚硝基脲盐酸盐）耐药的主要分子。另一方面，编码负责多药耐药的P-糖蛋白的mdr1和解毒酶GST-π的表达水平较低。MT的转录本，另一种可能与顺二氯二氨铂（II）（CDDP）耐药相关的用于细胞解毒的含硫醇分子，仅能微弱检测到。术后，患者最初接受静脉注射ACNU和依托泊苷（VP16）治疗，导致肿瘤有轻微消退反应。对于维持治疗，根据Northern印迹分析结果，我们将ACNU换成了CDDP。因此，残留肿瘤显示出明显反应，在接受两个疗程的CDDP和VP16全身化疗后几乎消失。
该病例中肿瘤的成功消退表明，对肿瘤组织中这些化疗耐药相关基因表达进行Northern印迹分析可为确定最佳抗癌药物以提高化疗疗效提供有益信息。
