Summary
Telomere maintenance has been shown to be essential for unlimited growth potential of human cells and is regarded as one hallmark of cancer. Telomere repeats at the ends of eukaryotic chromosomes are synthesized by the enzyme telomerase, which is active in most cancers and to some extend also in normal somatic cells. Therefore, targeting the telomerase/telomere complex offers great potential for the development of novel anticancer therapeutics. An example of such a strategy is the small molecule BIBR1532 that is a selective, non-nucleosidic inhibitor of the catalytic component hTERT. Treatment of cancer cells with this compound leads to progressive telomere shortening, consecutive telomere dysfunction, and finally growth arrest after a lag period that is largely dependent on initial telomere length. We have additionally shown that using this class of telomerase inhibitor at higher concentrations exerts a direct cytotoxic effect on malignant cells of the hematopoietic system but not on normal stem cells, which appears to derive from direct damage to the structure of individual telomeres.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Cech, T.R. (2004) Beginning to understand the end of the chromosome. Cell, 116, 273–9.
Griffith, J.D., Comeau, L., Rosenfield, S., Stansel, R.M., Bianchi, A., Moss, H. and de Lange, T. (1999) Mammalian telomeres end in a large duplex loop. Cell, 97, 503–14.
Cong, Y.S., Wright, W.E. and Shay, J.W. (2002) Human telomerase and its regulation. Microbiol Mol Biol Rev, 66, 407–25, table of contents.
Zimmermann, S. and UM, M. (2005) Telomere dynamics in hematopoietic stem cells. Curr Mol Med, 5, 179–85.
Shay, J.W. and Bacchetti, S. (1997) A survey of telomerase activity in human cancer. Eur J Cancer, 33, 787–91.
Kelland, L. (2005) Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics–current status and future prospects. Eur J Cancer, 41, 971–9.
Strahl, C. and Blackburn, E.H. (1994) The effects of nucleoside analogs on telomerase and telomeres in Tetrahymena. Nucleic Acids Res, 22, 893–900.
Damm, K., Hemmann, U., Garin-Chesa, P., Hauel, N., Kauffmann, I., Priepke, H., Niestroj, C., Daiber, C., Enenkel, B., Guilliard, B., Lauritsch, I., Muller, E., Pascolo, E., Sauter, G., Pantic, M., Martens, U.M., Wenz, C., Lingner, J., Kraut, N., Rettig, W.J. and Schnapp, A. (2001) A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J, 20, 6958–68.
Pascolo, E., Wenz, C., Lingner, J., Hauel, N., Priepke, H., Kauffmann, I., Garin-Chesa, P., Rettig, W.J., Damm, K. and Schnapp, A. (2002) Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate. J Biol Chem, 277, 15566–72.
El-Daly, H., Kull, M., Zimmermann, S., Pantic, M., Waller, C.F. and Martens, U.M. (2005) Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532. Blood, 105, 1742–9.
Rufer, N., Dragowska, W., Thornbury, G., Roosnek, E. and Lansdorp, P.M. (1998) Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat Biotechnol, 16, 743–7.
Blasco, M.A., Lee, H.W., Hande, M.P., Samper, E., Lansdorp, P.M., DePinho, R.A. and Greider, C.W. (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell, 91, 25–34.
Martens, U.M., Chavez, E.A., Poon, S.S., Schmoor, C. and Lansdorp, P.M. (2000) Accumulation of short telomeres in human fibroblasts prior to replicative senescence. Exp Cell Res, 256, 291–9.
Martens, U.M., Zijlmans, J.M., Poon, S.S., Dragowska, W., Yui, J., Chavez, E.A., Ward, R.K. and Lansdorp, P.M. (1998) Short telomeres on human chromosome 17p. Nat Genet, 18, 76–80.
Poon, S.S., Martens, U.M., Ward, R.K. and Lansdorp, P.M. (1999) Telomere length measurements using digital fluorescence microscopy. Cytometry, 36, 267–78.
Zijlmans, J.M., Martens, U.M., Poon, S.S., Raap, A.K., Tanke, H.J., Ward, R.K. and Lansdorp, P.M. (1997) Telomeres in the mouse have large inter-chromosomal variations in the number of T2AG3 repeats. Proc Natl Acad Sci USA, 94, 7423–8.
Acknowledgments
The authors thank Dr Stefan Zimmermann and Dr Milena Pantic for their kind advice and Dr Mike Harris for editing the manuscript. This work was supported by European Union (LSHC-CT-2004-502943), Sonderforschungsbereich 364 (Deutsche Forschungsgemeinschaft), Verein zur Leukaemieforschung, Freiburg, Germany.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Humana Press Inc.
About this protocol
Cite this protocol
Daly, H.E., Martens, U.M. (2007). Telomerase Inhibition and Telomere Targeting in Hematopoietic Cancer Cell Lines with Small Non-Nucleosidic Synthetic Compounds (BIBR1532). In: Andrews, L.G., Tollefsbol, T.O. (eds) Telomerase Inhibition. Methods in Molecular Biology™, vol 405. Humana Press. https://doi.org/10.1007/978-1-60327-070-0_6
Download citation
DOI: https://doi.org/10.1007/978-1-60327-070-0_6
Publisher Name: Humana Press
Print ISBN: 978-1-58829-683-2
Online ISBN: 978-1-60327-070-0
eBook Packages: Springer Protocols