Yabuno T, Konishi N, Nakamura M, Tsuzuki T, Tsunoda S, Sakaki T, Hiasa Y
Department of Neurosurgery, Nara Medical University, Kashihara, Japan.
J Neurooncol. 1998 Jan;36(2):105-12. doi: 10.1023/a:1005878402133.
To cast light on the mechanisms of drug-resistance, experimental brain tumors were immunohistochemically evaluated for expression of glutathione S-transferase (GST)-alpha, mu, pi, p-glycoprotein and apoptosis-related factors, such as bcl-2 and p53, as well as by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) method. Rat brain tumors induced by means of prenatal exposure to ethylnitrosourea (ENU) were treated with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and/or vincristine. Tumors more than 2 mm in size were considered to be drug resistant. The expression of GST-mu was strongly positive in ACNU-treated brain tumors, while p-glycoprotein was overexpressed in vincristine-treated brain tumors. Neither p53 nor bcl-2 expression directly correlated with apoptosis identified by TUNEL method, but tumors lacking apoptotic cells always demonstrated the expression of either GST-mu or p-glycoprotein. These results indicate that tumors resistant to chemotherapy might not be susceptible to induction of apoptosis, and therefore that mechanisms of drug resistance are related to programmed cell death in brain tumors.
为了阐明耐药机制，对实验性脑肿瘤进行免疫组织化学评估，检测谷胱甘肽S-转移酶（GST）-α、μ、π、P-糖蛋白以及凋亡相关因子如bcl-2和p53的表达，并采用末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记法（TUNEL法）。用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（ACNU）和/或长春新碱治疗经产前暴露于乙基亚硝基脲（ENU）诱导的大鼠脑肿瘤。大小超过2毫米的肿瘤被认为具有耐药性。GST-μ在接受ACNU治疗的脑肿瘤中表达强烈阳性，而P-糖蛋白在接受长春新碱治疗的脑肿瘤中过表达。p53和bcl-2的表达均与TUNEL法鉴定的凋亡无直接相关性，但缺乏凋亡细胞的肿瘤总是显示出GST-μ或P-糖蛋白的表达。这些结果表明，对化疗耐药的肿瘤可能不易诱导凋亡，因此耐药机制与脑肿瘤中的程序性细胞死亡有关。
