Development of a syngenic brain-tumor model resistant to chloroethyl-nitrosourea using a methylguanine DNA methyltransferase cDNA.
Development of a syngenic brain-tumor model resistant to chloroethyl-nitrosourea using a methylguanine DNA methyltransferase cDNA.
复制标题
使用甲基鸟嘌呤 DNA 甲基转移酶 cDNA 开发抗氯乙基亚硝基脲的同基因脑肿瘤模型。
作者：
Y. Manome;M. Watanabe;K. Futaki;H. Ishiguro;S. Iwagami;K. Noda;H. Dobashi;Y. Ochiai;Y. Ohara;K. Sanuki;T. Kunieda;T. Ohno
氯乙基亚硝基脲（CENU）是治疗脑肿瘤最有效的化疗药物之一。然而，对这种药物的获得性耐药性已经成为脑肿瘤患者治疗中的一个严重问题。耐药的主要机制是肿瘤细胞中O 6-甲基鸟嘌呤-DNA-甲基转移酶（MGMT）的募集。许多方法，包括用酶耗竭、抗体、反义物和核酶治疗，已被报道成功克服抗性。为了正确评估这些方法，我们设计了一个对CENU耐药的同系大鼠脑肿瘤模型。用逆转录病毒介导的方法将MGMT基因导入9 L大鼠胶质肉瘤细胞，并将其立体定向植入脑实质中。在该模型中，接种耐药细胞的大鼠在用CENU治疗后死亡明显早于对照细胞的大鼠。由于颅内空间有限，动物的存活率有限。由于存活率的敏感性和可重复性，该系统可能在评估耐药脑肿瘤的方法中发挥作用。
Chloroethyl-nitrosourea (CENU) is one of the most potent chemotherapeutic agents for brain tumors. However, acquired resistance to this drug has become a serious problem in the treatment of brain tumor patients. The main mechanism of the resistance is a recruitment of the O6-methylguanine-DNA- methyltransferase (MGMT) in tumor cells. Many approaches, including treatment with enzyme-depletions, antibodies, antisenses, and a ribozyme, have been reported to successfully overcome the resistance. In order to evaluate these approaches properly, we designed a syngenic rat brain-tumor model resistant to CENU. The 9L rat gliosarcoma cells were retrovirally transduced with MGMT cDNA and stereotactically implanted into the brain parenchyma. In this model, rats inoculated with resistant cells died significantly earlier than did rats with control cells after treatment with CENU. Because of the limited intracranial space, the animals presented a restricted survival. Since the survival was sensitive and reproducible, this system may have a role in the evaluation of approaches to drug-resistant brain-tumors.