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Treatment of bladder cancer cells in vitro and in vivo with 2–5A antisense telomerase RNA

Gene Therapy volume 8, pages 654–658 (2001)Cite this article

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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Authors and Affiliations

  1. Center for Surgery Research, The Cleveland Clinic Foundation, Cleveland, OH

    S Koga, Y Kondo, T Komata & S Kondo

  2. Department of Urology, Tokyo Women's Medical College, Shinjuku-ku, Tokyo, Japan

    S Koga

  3. Department of Neurosurgery, Mount Sinal School of Medicine, New York, NY

    Y Kondo, T Komata & S Kondo

  4. Department of Neurosurgery, The Cleveland Clinic Foundation, Cleveland, OH

    T Komata & S Kondo

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  1. S Koga
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  2. Y Kondo
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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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