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Breast Cancer Research and Treatment

, Volume 96, Issue 1, pp 73–81 | Cite as

Effects of a novel telomerase inhibitor, GRN163L, in human breast cancer

  • Ginelle C. Gellert
  • Z. Gunnur Dikmen
  • Woodring E. Wright
  • Sergei Gryaznov
  • Jerry W. Shay
Article

Summary

Telomerase activity is undetectable in most normal tissues but the vast majorities of cancers express active telomerase. Therefore, telomerase serves as an attractive target for the treatment of cancers. GRN163L is a lipid-modified oligonucleotide N3′→P5′ thio-phosphoramidate complementary to the RNA template region of human telomerase. The anti-telomerase activity of GRN163L was evaluated using MDA-MB-231 and MDA-MB-435 human breast adenocarcinoma cell lines. Twice weekly administration of GRN163L resulted in the inhibition of telomerase activity and progressive telomere shortening. Cells treated with GRN163L did not demonstrate decreased cell proliferation for up to 2 weeks. However, after additional treatment, cell proliferation gradually decreased in GRN163L-treated cells compared to untreated or mismatch control oligoncleotide treated cells. Furthermore, anti-tumorigenic effects were seen in cells treated with GRN163L, as cells lose their ability to form colonies in soft agar and were unable to form colonies in the clonal efficiency assay upon incubation with GRN163L. Moreover, breast cancer cells that were treated with GRN163L for only 1 week prior to plating in invasion chambers, and when bulk telomere are still long, exhibit significantly diminished invasive potential. These results reveal critical information regarding the effectiveness of GRN163L as a potential therapeutic agent for the treatment of human breast cancer.

Keywords

breast cancer oligonucleotide telomerase inhibitor therapeutics 

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Notes

Acknowledgements

The authors thank William Walker for technical assistance with TRF analysis. The work at UTSW is supported by Geron Corporation, Menlo Park, CA and CA70907. We also thank Dr. Krisztina Pongracz and Daria Zielinska for help with the initial oligonucleotide preparation.

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Copyright information

© Springer 2005

Authors and Affiliations

  • Ginelle C. Gellert
    • 1
  • Z. Gunnur Dikmen
    • 1
  • Woodring E. Wright
    • 1
  • Sergei Gryaznov
    • 2
  • Jerry W. Shay
    • 1
  1. 1.Department of Cell BiologyUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Geron CorporationMenlo ParkUSA

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