title: A highly selective telomerase inhibitor limiting human cancer cell proliferation.
abstract: 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.
authors.affiliation: Boehringer Ingelheim Pharma KG, Oncology Research, Birkendorfer Strasse 65, D-88397 Biberach, Germany. klaus.damm@bc.boehringer-ingelheim.com
authors.forename: K
authors.initials: K
authors.lastname: Damm
authors.forename: U
authors.initials: U
authors.lastname: Hemmann
authors.forename: P
authors.initials: P
authors.lastname: Garin-Chesa
authors.forename: N
authors.initials: N
authors.lastname: Hauel
authors.forename: I
authors.initials: I
authors.lastname: Kauffmann
authors.forename: H
authors.initials: H
authors.lastname: Priepke
authors.forename: C
authors.initials: C
authors.lastname: Niestroj
authors.forename: C
authors.initials: C
authors.lastname: Daiber
authors.forename: B
authors.initials: B
authors.lastname: Enenkel
authors.forename: B
authors.initials: B
authors.lastname: Guilliard
authors.forename: I
authors.initials: I
authors.lastname: Lauritsch
authors.forename: E
authors.initials: E
authors.lastname: Müller
authors.forename: E
authors.initials: E
authors.lastname: Pascolo
authors.forename: G
authors.initials: G
authors.lastname: Sauter
authors.forename: M
authors.initials: M
authors.lastname: Pantic
authors.forename: U M
authors.initials: UM
authors.lastname: Martens
authors.forename: C
authors.initials: C
authors.lastname: Wenz
authors.forename: J
authors.initials: J
authors.lastname: Lingner
authors.forename: N
authors.initials: N
authors.lastname: Kraut
authors.forename: W J
authors.initials: WJ
authors.lastname: Rettig
authors.forename: A
authors.initials: A
authors.lastname: Schnapp
mesh_terms: D002455:Cell Division / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D019098:Telomerase