锤头状核酶作用于人类胸苷酸合成酶对胸苷酸合成酶抑制剂细胞毒性的影响。
Effect of hammerhead ribozyme against human thymidylate synthase on the cytotoxicity of thymidylate synthase inhibitors.
作者信息
Kobayashi H, Takemura Y, Miyachi H, Skelton L, Jackman A L
机构信息
Department of Laboratory Medicine, National Defense Medical College, Saitama.
出版信息
Jpn J Cancer Res. 1995 Nov;86(11):1014-8. doi: 10.1111/j.1349-7006.1995.tb03014.x.
One of the resistance mechanisms to folate-based thymidylate synthase (TS) inhibitors is the increase in TS activity in tumor cells. Human B lymphoblastoid cell line (W1L2) was made resistant to a lipophilic non-polyglutamatable TS inhibitor (ZM249148), and the subline (W1L2:R179) showed a 20-fold increase in TS enzyme activity with concomitant overexpression of TS mRNA. To overcome the resistance, we designed a ribozyme that can cleave the CUC sequences in a triple tandemly repeated sequence of TS mRNA. Expression of this ribozyme in W1L2:R179 cells transfected with Epstein Barr virus-based expression vector resulted in sensitization to TS inhibitors concomitantly with a decrease of TS expression. The ribozyme expressed in transfectants was shown to be functional in cleaving artificial TS RNA in vitro.
对基于叶酸的胸苷酸合成酶（TS）抑制剂的一种耐药机制是肿瘤细胞中TS活性增加。使人B淋巴母细胞系（W1L2）对一种亲脂性不可聚谷氨酸化的TS抑制剂（ZM249148）产生耐药性，该亚系（W1L2:R179）的TS酶活性增加了20倍，同时TS mRNA过表达。为了克服耐药性，我们设计了一种核酶，它可以切割TS mRNA三联串联重复序列中的CUC序列。在用基于爱泼斯坦-巴尔病毒的表达载体转染的W1L2:R179细胞中表达这种核酶，导致对TS抑制剂敏感，同时TS表达降低。转染子中表达的核酶在体外切割人工TS RNA时显示出功能活性。
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