Treatment of prostate cancer in vitro and in vivo with 2-5A-anti-telomerase RNA component
Treatment of prostate cancer in vitro and in vivo with 2-5A-anti-telomerase RNA component
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DOI：
10.1038/sj.onc.1203538
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发表时间：
2000-04-27
期刊：
影响因子：
8
通讯作者：
Kondo, S
中科院分区：
文献类型：
--
作者：
Kondo, Y;Koga, S;Kondo, S
前列腺癌是美国老年男性最常见的恶性肿瘤。由于晚期前列腺癌没有根治性治疗，因此探索新的治疗方式至关重要。端粒酶是一种核糖核蛋白，在绝大多数前列腺癌中检测到，但在正常或良性前列腺增生组织中检测不到。因此，端粒酶有望成为前列腺癌靶向治疗的一个强有力的候选者。在这项研究中，我们合成了一个19-mer的反义寡核苷酸对RNA成分的人端粒酶（hTR）连接到一个2-5A分子（2-5A-anti-hTR），并研究其对前列腺癌细胞的细胞毒作用。2-5A反义策略依赖于在靶向RNA序列的位点处募集和激活RNase L。我们在此表明，在阳离子脂质体存在下用2- 5A-抗-hTR处理在6天内将测试的Turner细胞系的细胞活力降低至9-18%。相反，正常成纤维细胞仅对处理有抗性。其作用主要是通过激活caspase家族成员诱导细胞凋亡。2 - 5A-anti-hTR治疗裸鼠皮下移植瘤，可通过诱导肿瘤细胞凋亡抑制肿瘤生长（P < 0.001）。2-5A-anti-hTR治疗可能是一种有前景的端粒酶活性前列腺癌治疗方法。
Prostate cancer is the most common malignancy of elderly men in the United States. Since there is no curative treatment for advanced prostate cancer, exploration of novel modalities of treatment is essential. Telomerase, a ribsnucleoprotein, is detected in the vast majority of prostate cancer, but not in normal or benign prostatic hyperplasin tissues. Thus, telomerase is expected to be a very strong candidate for targeted therapy of prostate cancer. In this study, we synthesized a 19-mer antisense oligonucleotide against the RNA component of human telomerase (hTR) linked to a 2-5A molecule (2-5A-anti-hTR) and examined its cytotoxic effect on prostate cancer cells. The 2-5A antisense strategy relies on the recruitment and activation of RNase L at the site of targeted RNA sequence. We here show that treatment with 2-5A-anti-hTR in the presence of a cationic liposome reduced cell viability of turner cell lines tested to 9-18% within 6 days, In contrast, normal fibroblast cells mere resistant to the treatment. Its effect was mainly due to induction of apoptosis by activated caspase family members. Furthermore, treatment of subcutaneous tumors in nude mice with 2-SA-anti-hTR significantly suppressed the tumor growth through induction of apoptosis (P < 0.001), The treatment with 2-5A-anti-hTR may be a promising strategy for the treatment modality of prostate cancer with telomerase activity.