Advertisement

Telomerase as a Therapeutic Target

Therapeutic Potential of Telomerase Inhibitors
  • John A. Double
Part of the Methods in Molecular Biology™ book series (MIMB, volume 191)

Abstract

The most desirable properties of any therapeutic agent must be selectivity and potency (1). Of the two, potency is less critical, though in terms of potential administration it is important to recognize that patients should not be expected to take grams of material nor can the costs of producing large quantities be ignored.

Keywords

Telomere Length Therapeutic Index Peptide Nucleic Acid Cancer Process Cancer Drug Discovery 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Double, J. A. (1992) Selectivity and potency; are we doing the right things to find anti-cancer agents with these properties? Br. J. Cancer 65, 143–144.PubMedCrossRefGoogle Scholar
  2. 2.
    Kim, N. W., Piatyszek, M. A., Prowse, K. R., et al. (1994) Specific association of human telomerase activity with immortal cells and cancer. Science, 266, 2011–2015.PubMedCrossRefGoogle Scholar
  3. 3.
    Kim, N. W. (1997) Clinical implications of telomerase in Cancer. Eur. J. Cancer 33, 781–786.PubMedCrossRefGoogle Scholar
  4. 4.
    Duncan, V. E., Ajmani, P. S., and Hughes, J. A. (1998) Cellular delivery is a major obstacle for oligodeoxynucleotide inhibition of telomerase activity. Anticancer Res. 18, 4105–4108.PubMedGoogle Scholar
  5. 5.
    Holt, S. E., Shay, J. W., and Woodring, E. W. (1996) Refining the telomere-telomerase hypothesis of aging and cancer. Nat. Biotechnol. 14, 836–839.PubMedCrossRefGoogle Scholar
  6. 6.
    Kato, H., Ando, T., Hongo, H., et al. (1999) Telomerase activity and its subunitgenes (hTERC, hTERT) expression related to histological atypias in human colorectral adenomas. Gastroenterology 116, G1905.Google Scholar
  7. 7.
    Nemoto, K., Kondo, Y., Himeno, S., et al. (2000) Modulation of telomerase activity by zinc in human prostatic and renal cancer cells. Biochem. Pharmacol. 59, 401–405.PubMedCrossRefGoogle Scholar
  8. 8.
    Tamura, Y., Tao, M., Miyano-Kurosaki, N., Takai, K. and Takaku, H. (2000) Inhibition of human telomerase activity by antisense phosphorothioate oligonucleotides encapsulated with the transfection reagent, FuGENE™ 6, in HeLa cells. Antisense Nucleic Acid Drug Dev. 10, 87–96.PubMedCrossRefGoogle Scholar
  9. 9.
    Tao, M., Miyano-Kurosaki, N., Takai, K., and Takaku, H. (1999). Specific inhibition of human telomerase activity by transfection reagent, FuGENE6-antisense phosphorothioate oligonucleotide complex in HeLa cells. FEBS Lett. 454, 312–316.PubMedCrossRefGoogle Scholar
  10. 10.
    Togashi, K., Kakeya, H., Morishita, M., Song, Y. X., and Osada, H. (1998). Inhibition of human telomerase activity by alterperylenol. Oncol. Res. 10, 449–453.PubMedGoogle Scholar
  11. 11.
    Yokoyama, Y., Takahashi, Y., Shinohara, A., Wan, X. Y., Takahashi, S., Niwa, K., and Tamaya, T. (2000) The 5-end of hTERT mRNA is a good target for hammerhead ribozyme to suppress telomerase activity. Biochem. Biophys. Res. Commun. 273, 316–321.PubMedCrossRefGoogle Scholar
  12. 12.
    Harley, C. B., Kim, N. W., Prowse, K. R., et al. (1994) Telomerase, cell immortality and cancer. Cold Spring Harbor Symp. Quant. Biol. 59, 307–315.PubMedGoogle Scholar
  13. 13.
    Burger, A. M., Bibby, M. C., and Double, J. A. (1997) Telomerase activity in normal and malignant mammalian tissues: feasibility of telomerase as a target for cancer chemotherapy. Br. J. Cancer 75, 516–522.PubMedCrossRefGoogle Scholar
  14. 14.
    Strahl, C. and Blackburn, E. H. (1994) The effects of nucleoside anaogs on telomerase and telomeres in Tetrahymena. Nucleic Acids Res. 22, 893–900.CrossRefGoogle Scholar
  15. 15.
    Strahl, C. and Blackburn, E. H. (1996) Effect of reverse transcriptase inhibiution on telomere length and telomerase activity in two immortalized human cell lines. Mol. Cell Biol. 16, 53–65.PubMedGoogle Scholar
  16. 16.
    Feng, J., Funk, W. D., Wang, S. S., et al. (1995) The RNA component of human telomerase. Science 269, 1236–1241.PubMedCrossRefGoogle Scholar
  17. 17.
    Folini, M., Colella, G., Villa, R., Lualdi, S., Daidone, M. G., and Zaffaroni, N. (2000) Inhibition of telomerase activity by a hammer-head ribozyme targeting the RNA component of telomerase in human melanoma cells. J. Invest. Dermatol. 114, 259–267.PubMedCrossRefGoogle Scholar
  18. 18.
    Heicappell, R., Sachsinger, J., Krause, H., Muller, M., and Miller, K. (1999) Inhibition of telomerase activity by antisense oligonucleotides in renal cell carcinoma. Eur. J. Cancer 35, 1404.Google Scholar
  19. 19.
    Norton, J. C., Piatyszek, M. A., Wright, W. E., Shay, J. W., and Corey, D. R. (1996) Inhibition of human telomerase activity by peptide nucleic acids. Nat. Biotechnol. 14, 615–619.PubMedCrossRefGoogle Scholar
  20. 20.
    Villa, R., Folini, M., Lualdi, S., Veronese, S., Daidone, M. G., and Zaffaroni, N. (2000) Inhibition of telomerase activity by a cell-penetrating peptide nucleic acid construct in human melanoma cells. FEBS Lett. 473, 241–248.PubMedCrossRefGoogle Scholar
  21. 21.
    Burger, A. M., Double, J. A., and Newell, D. R. (1997) Inhibition of telomerase activity by cisplatin in human testicular cancer cells. Eur. J. Cancer 33, 638–644.PubMedCrossRefGoogle Scholar
  22. 22.
    Sherman, S.E. and Lippard, S.J. (1987) Structural aspects of platinum anti-cancer drug-interactions with DNA. Chem Rev 87, 1153–1181.CrossRefGoogle Scholar
  23. 23.
    Akiyama, M., Horiguchi-Yamada, J., Saito, S., et al. (1999) Cytostatic concentrations of anticancer agents do not affect telomerase activity of leukaemic cells in vitro. Eur. J. Cancer, 35, 309–315.PubMedCrossRefGoogle Scholar
  24. 24.
    Kiyozuka, Y., Yamamoto, D., Yang, J. H., et al. (2000) Correlation of chemosensitivity to anticancer drugs and telomere length, telomerase activity and telomerase RNA expression in human ovarian cancer cells. Anticancer Res. 20, 203–212.PubMedGoogle Scholar
  25. 25.
    Murakami, J., Nagai, N., Shigemasa, K., and Ohama, K. (1999) Inhibition of telomerase activity and cell proliferation by a reverse tran-scriptase inhibitor in gynaecological cancer cell lines. Eur. J. Cancer 35, 1027–1034.PubMedCrossRefGoogle Scholar
  26. 26.
    Villa, R., Folini, M., Perego, P., et al. (2000) Telomerase activity and telomere length in human ovarian cancer and melanoma cell lines: Correlation with sensitivity to DNA damaging agents. Int. J. Oncol. 16, 995–1002.PubMedGoogle Scholar
  27. 27.
    Akiyama, M., Yamada, O., Akita, S., et al. (2000) Ectopic expression of c-myc fails to overcome downregulation of telomerase activity induced by herbimycin A, but ectopic hTERT expression overcomes it. Leukemia 14, 1260–1265.PubMedCrossRefGoogle Scholar
  28. 28.
    Colgin, L. M., Wilkinson, C., Englezou, A., et al. (2000). The hTERT alpha splice variant is a dominant negative inhibitor of telomerase activity. Neoplasia 2, 426–432.PubMedCrossRefGoogle Scholar
  29. 29.
    Koyanagi, Y., Kobayashi, D., Yajima, T., et al. (2000) Telomerase activity is down regulated via decreases in hTERT mRNA but not TEP1 mRNA or hTERC during the differentiation of leukemic cells. Anticancer Res. 20, 773–778.PubMedGoogle Scholar
  30. 30.
    Liu, K., Hodes, R. J., and Weng, N. P. (2000) Dissociation between telomerase reverse transcriptase (hTERT) expression and telomerase activity in human lymphocytes. FASEB J. 14, A1170–A1170.Google Scholar
  31. 31.
    Yan, P., Saraga, E. P., Bouzourene, H., Bosman, F. T., and Benhattar, J. (2001) Expression of telomerase genes correlates with telomerase activity in human colorectal carcinogenesis. J. Pathol. 193, 21–26.PubMedCrossRefGoogle Scholar
  32. 32.
    Ahmed, S. and Hodgkin, J. (2000) MRT-2 checkpoint protein is required for germline immortality and telomere replication in Celegans. Nature 403, 159–164.PubMedCrossRefGoogle Scholar
  33. 33.
    Blackburn, E. H. (2000). Telomere states and cell fates. Nature 408, 53–56.PubMedCrossRefGoogle Scholar
  34. 34.
    Shore, D. (2001). Telomeric chromatin: replicating and wrapping up chromosome ends. Curr. Opin. Genet. Dev. 11, 189–198.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2002

Authors and Affiliations

  • John A. Double
    • 1
  1. 1.Cancer Research UnitUniversity of BradfordBradfordUK

Personalised recommendations