title: In vivo inhibition of lung cancer by GRN163L: a novel human telomerase inhibitor.
abstract: Differential regulation of telomerase activity in normal and tumor cells provides a rationale for the design of new classes of telomerase inhibitors. The telomerase enzyme complex presents multiple potential sites for the development of inhibitors. GRN163L, a telomerase enzyme antagonist, is a lipid-modified 13-mer oligonucleotide N3' --> P5'-thio-phosphoramidate, complementary to the template region of telomerase RNA (hTR). We evaluated both the in vitro and in vivo effects of GRN163L using A549-luciferase (A549-Luc) human lung cancer cells expressing a luciferase reporter. GRN163L (1 micromol/L) effectively inhibits telomerase activity of A549-Luc cells, resulting in progressive telomere shortening. GRN163L treatment also reduces colony formation in soft agar assays. Surprisingly, after only 1 week of treatment with GRN163L, A549-Luc cells were unable to form robust colonies in the clonal efficiency assay, whereas the mismatch control compound had no effect. Finally, we show that in vivo treatment with GRN163L is effective in preventing lung metastases in xenograft animal models. These in vitro and in vivo data support the development of GRN163L as a therapeutic for the treatment of cancer.
authors.affiliation: University of Hacettepe, Faculty of Medicine, Department of Biochemistry, Ankara, Turkey.
authors.forename: Z Gunnur
authors.initials: ZG
authors.lastname: Dikmen
authors.forename: Ginelle C
authors.initials: GC
authors.lastname: Gellert
authors.forename: Shalmica
authors.initials: S
authors.lastname: Jackson
authors.forename: Sergei
authors.initials: S
authors.lastname: Gryaznov
authors.forename: Robert
authors.initials: R
authors.lastname: Tressler
authors.forename: Pakize
authors.initials: P
authors.lastname: Dogan
authors.forename: Woodring E
authors.initials: WE
authors.lastname: Wright
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D008081:Liposomes; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013462:Sulfur Radioisotopes; D019098:Telomerase / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; C479222:GRN163; D008081:Liposomes; D009841:Oligonucleotides; D013462:Sulfur Radioisotopes; D008156:Luciferases; D019098:Telomerase