Mineura K, Fushimi S, Kowada M, Isowa G, Ishizaki K, Ikenaga M
Neurosurgical Service, Akita University Hospital, Japan.
Acta Neurochir (Wien). 1990;103(1-2):62-6. doi: 10.1007/BF01420193.
We have examined O6-methylguanine-DNA methyltransferase (O6-MT) activity of rat brain tumour cell strains with reference to cellular resistance to antitumour nitrosoureas, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (nimustine, ACNU) and methyl-6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyrano side (ramustine, MCNU). The values of O6-MT activity were 52 and 160 fmol/mg protein extract in 9L and C6 rat brain tumour cells, respectively; while HeLa S3 cells, as a methyl excision repair positive (Mer+) cell strain, revealed a rather high value of 488 fmol/mg. 9L cells indicative of a low O6-MT activity showed 13 microM for ACNU and 18 microM for MCNU at a 10% survival dose (SD10), determined by a clonogenic cell assay as an index of cellular resistance. In contrast to this, C6 cells revealed a SD10 value of 67 microM and 36 microM for ACNU and MCNU, respectively, indicating higher resistance than 9L cells. HeLa S3 cells showed the highest SD10 value as follows: 84 microM for ACNU and 73 microM for MCNU. The relationship between the O6-MT activity and the cellular resistance was almost linear, with relatively resistant cell lines exhibiting the higher levels of the O6-MT activity. This correlation between the O6-MT activity and the cellular resistance to nitrosoureas as ACNU and MCNU was not observed among other antitumour drugs, which included bleomycin (BLM), neocarzinostatin (NCS), cis-diamminedichloroplatinum (II) (CDDP), and etoposide (VP-16) in clinical use for brain tumour chemotherapy. This indicates that O6-MT activity can be an indicator of cellular resistance to antitumour nitrosoureas in the chemotherapy of brain tumours.
我们参照大鼠脑肿瘤细胞株对抗肿瘤亚硝基脲类药物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（尼莫司汀，ACNU）和甲基-6-[3-(2-氯乙基)-3-亚硝基脲基]-6-脱氧-α-D-吡喃葡萄糖苷（雷莫司汀，MCNU）的细胞耐药性，检测了大鼠脑肿瘤细胞株的O6-甲基鸟嘌呤-DNA甲基转移酶（O6-MT）活性。9L和C6大鼠脑肿瘤细胞中O6-MT活性值分别为52和160 fmol/mg蛋白提取物；而作为甲基切除修复阳性（Mer+）细胞株的HeLa S3细胞，其O6-MT活性值相当高，为488 fmol/mg。通过克隆形成细胞试验测定作为细胞耐药性指标的10%存活剂量（SD10），显示O6-MT活性较低的9L细胞对ACNU的SD10为13 μM，对MCNU的SD10为18 μM。与此相反，C6细胞对ACNU和MCNU的SD10值分别为67 μM和36 μM，表明其耐药性高于9L细胞。HeLa S3细胞显示出最高的SD10值如下：对ACNU为84 μM，对MCNU为73 μM。O6-MT活性与细胞耐药性之间的关系几乎呈线性，耐药性相对较高的细胞系表现出较高水平的O6-MT活性。在包括博来霉素（BLM）、新制癌菌素（NCS）、顺二氨二氯铂（II）（CDDP）和依托泊苷（VP-16）等临床上用于脑肿瘤化疗的其他抗肿瘤药物中，未观察到O6-MT活性与细胞对ACNU和MCNU等亚硝基脲类药物的耐药性之间的这种相关性。这表明在脑肿瘤化疗中，O6-MT活性可以作为细胞对抗肿瘤亚硝基脲类药物耐药性的一个指标。
