Chen Zhi, Koeneman Kenneth S, Corey David R
Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041, USA.
Cancer Res. 2003 Sep 15;63(18):5917-25.
Telomerase is expressed in most types of tumor cells but not in most somatic cells, suggesting that telomerase inhibitors may be a powerful new approach to cancer chemotherapy. Here we explore this hypothesis by treating cultured human tumor cells with a 2'-O-methoxyethyl oligonucleotide that binds the telomerase RNA template and acts as a potent inhibitor. Treatment of DU145 (Rb(-), p53(-)) and LNCaP (Rb(+), p53(+)) cells causes telomeres to shorten and cell proliferation to stop. Decreased cell proliferation in culture is not observed immediately but occurs after several weeks and is accompanied by telomere shortening. Antiproliferative effects are more profound for cells growing in soft agar or in colony formation assays, with 90% reduction in the colony-forming ability of LNCaP cells after less than 2 weeks of exposure to the inhibitor. Decreased growth of DU145 and LNCaP tumors and large reductions in prostate-specific antigen levels are also observed in vivo in xenograft models. Short-term treatment of cells with telomerase inhibitors does not increase the effects of standard antiproliferative agents paclitaxel, doxorubicin, etoposide, cisplatin, or carboplatin. Long-term inhibition and telomere shortening sensitize DU145 cells, but not LNCaP cells, to cisplatin or carboplatin. These results demonstrate that methoxyethyl oligomers directed against the template region of telomerase are potent agents and that significant antiproliferative effects can be observed after 2-3 weeks of treatment. Reduced cell proliferation and tumor growth support the hypothesis that telomerase inhibition can make a useful contribution to chemotherapy and should encourage broad testing of telomerase inhibitors.
端粒酶在大多数类型的肿瘤细胞中表达，但在大多数体细胞中不表达，这表明端粒酶抑制剂可能是癌症化疗的一种强有力的新方法。在这里，我们通过用一种与端粒酶RNA模板结合并作为强效抑制剂的2'-O-甲氧基乙基寡核苷酸处理培养的人肿瘤细胞来探索这一假设。用该抑制剂处理DU145（Rb(-)，p53(-)）和LNCaP（Rb(+)，p53(+)）细胞会导致端粒缩短和细胞增殖停止。培养中细胞增殖的减少不是立即观察到的，而是在几周后发生，并伴随着端粒缩短。在软琼脂中生长或进行集落形成试验的细胞中，抗增殖作用更为显著，LNCaP细胞在暴露于抑制剂不到2周后，其集落形成能力降低了90%。在异种移植模型的体内实验中，也观察到DU145和LNCaP肿瘤的生长减缓以及前列腺特异性抗原水平的大幅降低。用端粒酶抑制剂对细胞进行短期处理不会增强标准抗增殖药物紫杉醇、阿霉素、依托泊苷、顺铂或卡铂的作用。长期抑制和端粒缩短使DU145细胞对顺铂或卡铂敏感，但LNCaP细胞不敏感。这些结果表明，针对端粒酶模板区域的甲氧基乙基寡聚物是强效药物，并且在处理2 - 3周后可观察到显著的抗增殖作用。细胞增殖和肿瘤生长的减少支持了端粒酶抑制可为化疗做出有益贡献的假设，并应鼓励对端粒酶抑制剂进行广泛测试。
