Abstract
Bladder cancer is the most common malignant tumor of the urinary tract. Novel treatment approaches are essential because of the failure of current treatment options to cure a high percentage of patients. Telomerase, a ribonucleoprotein, is detected in almost all bladder cancer, but not in normal bladder tissues. Therefore, telomerase is expected to be a very promising candidate for targeted therapy of bladder 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 investigated its antitumor effect against bladder cancer cells. The 2–5A antisense strategy relies on the recruitment and activation of RNase L at the site of targeted RNA sequence. Here we demonstrate that treatment with 2–5A-anti-hTR reduced the viability of seven bladder cancer cell lines (UM-UC-2, UM-UC-3, UM-UC-6, UM-UC-9, UM-UC-14, RT4 and T24) expressing telomerase activity to 21–55% within 4 days. The cytotoxicity was mainly due to induction of caspase-dependent apoptosis. In contrast, normal fibroblast WI38 cells lacking telomerase activity were resistant to the treatment. Furthermore, treatment of subcutaneous UM-UC-2 tumors in nude mice with 2–5A-anti-hTR significantly suppressed the tumor growth through induction of apoptosis (P < 0.001). These findings may offer a strong support to the feasibility of the 2–5A-anti-hTR treatment for human bladder cancer.
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Acknowledgements
We thank Dr Robert H Silverman and Dr John K Cowell (Cleveland Clinic, Cleveland, OH, USA) for a gift of 2–5A-anti-hTR. We also thank Dr H Barton Grossman for bladder cancer cell lines. This study was supported in part by Cleveland Clinic Foundation Research Fund No. 5928 (SK).
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Koga, S., Kondo, Y., Komata, T. et al. Treatment of bladder cancer cells in vitro and in vivo with 2–5A antisense telomerase RNA. Gene Ther 8, 654–658 (2001). https://doi.org/10.1038/sj.gt.3301449
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DOI: https://doi.org/10.1038/sj.gt.3301449
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