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  • The EMBO Journal (2001) 20, 6958 - 6968
  • doi:10.1093/emboj/20.24.6958

A highly selective telomerase inhibitor limiting human cancer cell proliferation

Klaus Damm1,2, Ulrike Hemmann3,4, Pilar Garin-Chesa2, Norbert Hauel5, Iris Kauffmann5, Henning Priepke5, Claudia Niestroj2, Christine Daiber2, Barbara Enenkel2, Bernd Guilliard2, Ines Lauritsch2, Elfriede Müller2, Emanuelle Pascolo2, Gabriele Sauter2, Milena Pantic6,7, Uwe M. Martens6, Christian Wenz8, Joachim Lingner8, Norbert Kraut3, Wolfgang J. Rettig9 and Andreas Schnapp2

  1. Boehringer Ingelheim Pharma KG, Birkendorfer Strasse 65, D-88397 Biberach, Germany
  2. Oncology Research, Birkendorfer Strasse 65, D-88397 Biberach, Germany
  3. Genomics, Birkendorfer Strasse 65, D-88397 Biberach, Germany
  4. Present address: Aventis Pharma GmbH, Fraunhofer Strasse 13, D-82152 Martinsried, Germany
  5. Chemistry, Birkendorfer Strasse 65, D-88397 Biberach, Germany
  6. University Medical Center, Department for Hematology/Oncology, Hugstetterstrasse 55, D-79106 Freiburg i. Br., Germany
  7. Albert-Ludwigs-University, Department of Biology, D-79106 Freiburg i. Br., Germany
  8. Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland
  9. Boehringer Ingelheim Austria GmbH, Dr. Boehringer-Gasse 5–11, A-1120 Vienna, Austria

Correspondence to:

Klaus Damm, E-mail: klaus.damm@bc.boehringer-ingelheim.com

Received 11 September 2001; Accepted 26 October 2001; Revised 23 October 2001

Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model. This model was also used to demonstrate in vivo efficacy with no adverse side effects and uncomplicated oral administration of the inhibitor. These findings indicate that potent and selective, non-nucleosidic telomerase inhibitors can be designed as novel cancer treatment modalities.

  • Keywords:

    • cancer,
    • inhibitor,
    • microarray,
    • senescence,
    • telomerase