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  • Acquired Diseases
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Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53

Gene Therapy volume 7, pages 2071–2079 (2000)Cite this article

Abstract

Malignant gliomas of astrocytic origin have commonly expressed several features such as alterations in the tumor-suppressor gene p53 or p16 or the acquisition of telomerase activity, which are distinctive from astrocytes. Therefore, restoration of the tumor-suppressor gene or telomerase inhibition is expected to provide a cure for malignant gliomas. We have recently demonstrated that the treatment with a 19-mer antisense oligonucleotide against human telomerase RNA linked to a 2′,5′-oligoadenylate (2-5A-anti-hTR) inhibited the growth of malignant glioma cells. From a therapeutic point of view, it is very important to investigate the antitumor efficacy of 2-5A-anti-hTR combined with the restoration of p53 or p16 gene. In this study, we evaluated the antitumor effect of 2-5A-anti-hTR in combination with recombinant adenoviruses bearing p53, its associated p21WAF1/CIP1, or p16CDKN2 gene (Ad5CMV-p53, Ad5CMV-p21, or Ad5CMV-p16) against malignant glioma cells in vitro and in vivo. Five malignant glioma cell lines expressing the mutant p53 gene (A172, GB-1, T98G, U251-MG and U373-MG) were more sensitive to the combination of 2-5A-anti-hTR and Ad5CMV-p53 than to other combinations. The additive effect of the combination therapy was due to induction of caspase-dependent apoptosis and cell growth arrest. Furthermore, the 2-5A-anti-hTR treatment when combined with Ad5CMV-p53 showed greater efficacy against subcutaneous U251-MG tumors in nude mice. In contrast, U87-MG cells expressing the wild-type p53 gene were insensitive to Ad5CMV-p53, although the treatment with 2-5A-anti-hTR was significantly effective. These results indicate that combining 2-5A-anti-hTR with Ad5CMV-p53 has the most therapeutic potential for malignant gliomas with mutant p53. For tumors exhibiting wild-type p53, it may be useful to treat with 2-5A-anti-hTR.

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Acknowledgements

We thank Dr Masahiro Hitomi and Dr Isabelle Germano for critical reviews. We also thank Drs Robert H Silverman and John K Cowell for a gift of 2-5A-anti-hTR, and Drs Tatsuo Morimura and Akiko Nishiyama for GB-1 and U251-MG cells. This study was supported in part by Cleveland Clinic Foundation Research Fund No. 5928 (SK), the John Gagliarducci Fund (SK), and the United States Public Health Service Grant (1R01CA80233) (SK) awarded by the National Cancer Institute.

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Authors and Affiliations

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

    T Komata, Y Kondo, S Koga & S Kondo

  2. Department of Neurosurgery, The Cleveland Clinic Foundation, Cleveland, OH, USA

    T Komata & S Kondo

  3. Department of Neurosurgery, The Mount Sinai Medical Center, New York, NY, USA

    T Komata, Y Kondo & S Kondo

  4. Urology, Tokyo Women's Medical College, Shinjuku-ku, Tokyo, Japan

    S Koga

  5. Department of Urology, Molecular Urology and Therapeutics Program, University of Virginia, Charlottesville, VA, USA

    S C Ko & L W K Chung

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Komata, T., Kondo, Y., Koga, S. et al. Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53. Gene Ther 7, 2071–2079 (2000). https://doi.org/10.1038/sj.gt.3301327

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