Skip to main content
SpringerLink
Log in

Imetelstat (GRN163L) - Telomerase-Based Cancer Therapy

  • Chapter
  • First Online:
Book cover Small Molecules in Oncology

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 184))

Abstract

Telomeres and telomerase play essential roles in the regulation of the lifespan of human cells. While normal human somatic cells do not or only transiently express telomerase and therefore shorten their telomeres with each cell division, most human cancer cells typically express high levels of telomerase and show unlimited cell proliferation. High telomerase expression allows cells to proliferate and expand long-term and therefore supports tumor growth. Owing to the high expression and its role, telomerase has become an attractive diagnostic and therapeutic cancer target. Imetelstat (GRN163L) is a potent and specific telomerase inhibitor and so far the only drug of its class in clinical trials. Here, we report on the structure and the mechanism of action of imetelstat as well as about the preclinical and clinical data and future prospects using imetelstat in cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 199.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 259.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Akiyama M, Hideshima T, Shammas MA, Hayashi T, Hamasaki M, Tai YT, Richardson P, Gryaznov S, Munshi NC, Anderson KC (2003) Effects of oligonucleotide N3’–P5’ thio-phosphoramidate (GRN163) targeting telomerase RNA in human multiple myeloma cells. Cancer Res 63: 6187–6194

    PubMed  CAS  Google Scholar 

  • Alter BP, Baerlocher GM, Savage SA, Chanock SJ, Weksler BB, Willner JP, Peters JA, Giri N, Lansdorp PM (2007) Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood 110:1439–1447

    Article  PubMed  CAS  Google Scholar 

  • Armanios M, Greider CW (2005) Telomerase and cancer stem cells. Cold Spring Harb Symp Quant Biol 70:205–208

    Article  PubMed  CAS  Google Scholar 

  • Asai A, Oshima Y, Yamamoto Y, Uochi TA, Kusaka H, Akinaga S, Yamashita Y, Pongracz K, Pruzan R, Wunder E, Piatyszek M, Li S, Chin AC, Harley CB, Gryaznov S (2003) A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res 63:3931–3939

    PubMed  CAS  Google Scholar 

  • Baerlocher GM, Lansdorp PM (2003) Telomere length measurements in leukocyte subsets by automated multicolor flow-FISH. Cytometry 55A:1–6

    Article  CAS  Google Scholar 

  • Baerlocher GM, Mak J, Röth A, Rice KS, Lansdorp PM (2003) Telomere shortening in leukocyte subpopulations from baboons. J Leukoc Biol 73: 289–296

    Article  PubMed  CAS  Google Scholar 

  • Baerlocher GM, Mak J, Tien T, Lansdorp PM (2002) Telomere length measurement by fluorescence in situ hybridization and flow cytometry: tips and pitfalls. Cytometry 47:89–99

    Article  PubMed  CAS  Google Scholar 

  • Baerlocher GM, Vulto I, de Jong G, Lansdorp PM (2006) Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat Protocols 1:2365–2376

    Article  CAS  Google Scholar 

  • Barma DK, Elayadi A, Falck JR, Corey DR (2003) Inhibition of telomerase by BIBR 1532 and related analogues. Bioorg Med Chem Lett 13: 1333–1336

    Article  PubMed  CAS  Google Scholar 

  • Baumann P, Cech TR (2001) Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292:1171–1175

    Article  PubMed  CAS  Google Scholar 

  • Blackburn EH (1991) Structure and function of telomeres. Nature 350:569–573

    Article  PubMed  CAS  Google Scholar 

  • Blackburn EH (1992) Telomerases. Annu Rev Biochem 61:113–129

    Article  PubMed  CAS  Google Scholar 

  • Blackburn EH (2000) Telomere states and cell fates. Nature 408:53–56

    Article  PubMed  CAS  Google Scholar 

  • Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279:349–352

    Article  PubMed  CAS  Google Scholar 

  • Campisi J (2003) Cancer and ageing: rival demons? Nat Rev Cancer 3:339–349

    Article  PubMed  CAS  Google Scholar 

  • Chanan-Khan AA, Munshi NC, Hussein MA, Elias L, Benedetti F, Smith J, Khor SP, Huff CA (2008) Results of a Phase I Study of GRN163L, a Direct Inhibitor of Telomerase, in Patients with Relapsed and Refractory Multiple Myeloma (MM). ASH Annu Meet Abstr 112:3688

    Google Scholar 

  • Chang E, Harley CB (1995) Telomere length and replicative aging in human vascular tissues. Proc Natl Acad Sci U S A 92:11190–11194

    Article  PubMed  CAS  Google Scholar 

  • Chiu CP, Dragowska W, Kim NW, Vaziri H, Yui J, Thomas TE, Harley CB, Lansdorp PM (1996) Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells 14:239–248

    Article  PubMed  CAS  Google Scholar 

  • Collins K, Mitchell JR (2002) Telomerase in the human organism. Oncogene 21:564–579

    Article  PubMed  CAS  Google Scholar 

  • Cotter FE (1999) Antisense therapy of hematologic malignancies. Semin Hematol 36:9–14

    PubMed  CAS  Google Scholar 

  • d’Adda dF, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198

    Google Scholar 

  • 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 UM, Wenz C, Lingner J, Kraut N, Rettig WJ, Schnapp A (2001) A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J 20:6958–6968

    Article  PubMed  CAS  Google Scholar 

  • de Lange T (2002) Protection of mammalian telomeres. Oncogene 21:532–540

    Article  PubMed  Google Scholar 

  • Dikmen ZG, Gellert GC, Jackson S, Gryaznov S, Tressler R, Dogan P, Wright WE, Shay JW (2005) In vivo inhibition of lung cancer by GRN163L: a novel human telomerase inhibitor. Cancer Res 65:7866–7873

    PubMed  CAS  Google Scholar 

  • Dikmen ZG, Wright WE, Shay JW, Gryaznov SM (2008) Telomerase targeted oligonucleotide thio-phosphoramidates in T24-luc bladder cancer cells. J Cell Biochem 104:444–452

    Article  PubMed  CAS  Google Scholar 

  • Djojosubroto MW, Chin AC, Go N, Schaetzlein S, Manns MP, Gryaznov S, Harley CB, Rudolph KL (2005) Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma. Hepatology 42:1127–1136

    Article  PubMed  CAS  Google Scholar 

  • El Daly H, Kull M, Zimmermann S, Pantic M, Waller CF, Martens UM (2005) Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532. Blood 105:1742–1749

    Article  PubMed  CAS  Google Scholar 

  • Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP, Adams RR, Chang E, Allsopp RC, Yu J (1995) The RNA component of human telomerase. Science 269:1236–1241

    Article  PubMed  CAS  Google Scholar 

  • Fletcher TM, Cathers BE, Ravikumar KS, Mamiya BM, Kerwin SM (2001) Inhibition of human telomerase by 7-deaza-2’-deoxyguanosine nucleoside triphosphate analogs: potent inhibition by 6-thio-7-deaza-2’-deoxyguanosine 5’-triphosphate. Bioorg Chem 29:36–55

    Article  PubMed  CAS  Google Scholar 

  • Folini M, Colella G, Villa R, Lualdi S, Daidone MG, Zaffaroni N (2000) Inhibition of telomerase activity by a hammerhead ribozyme targeting the RNA component of telomerase in human melanoma cells. J Invest Dermatol 114:259–267

    Article  PubMed  CAS  Google Scholar 

  • Folini M, Pennati M, Zaffaroni N (2002) Targeting human telomerase by antisense oligonucleotides and ribozymes. Curr Med Chem Anticancer Agents 2:605–612

    Article  PubMed  CAS  Google Scholar 

  • Garcia CK, Wright WE, Shay JW (2007) Human diseases of telomerase dysfunction: insights into tissue aging. Nucleic Acids Res 35: 7406–7416

    Article  PubMed  CAS  Google Scholar 

  • Gellert GC, Dikmen ZG, Wright WE, Gryaznov S, Shay JW (2006) Effects of a novel telomerase inhibitor, GRN163L, in human breast cancer. Breast Cancer Res Treat 96:73–81

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Millan J, Goldblatt EM, Gryaznov SM, Mendonca MS, Herbert BS (2006) Specific telomere dysfunction induced by GRN163L increases radiation sensitivity in breast cancer cells. Int J Radiat Oncol Biol Phys 67(3):897–905

    PubMed  Google Scholar 

  • Griffith J, Comeau L, Rosenfield S, Stansel R, Bianchi A, Moss H, de Lange T (1999) Mammalian telomeres end in a large duplex loop. Cell 97:503–514

    Article  PubMed  CAS  Google Scholar 

  • Gryaznov SM, Jackson S, Dikmen G, Harley C, Herbert BS, Wright WE, Shay JW (2007) Oligo­nucleotide conjugate GRN163L targeting human telomerase as potential anticancer and antimetastatic agent. Nucleosides Nucleotides Nucleic Acids 26: 1577–1579

    Article  PubMed  CAS  Google Scholar 

  • Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA (1999a) Creation of human tumour cells with defined genetic elements. Nature 400:464–468

    Article  PubMed  CAS  Google Scholar 

  • Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, Beijersbergen RL, Knoll JH, Meyerson M, Weinberg RA (1999b) Inhibition of telomerase limits the growth of human cancer cells. Nat Med 5:1164–1170

    Article  PubMed  CAS  Google Scholar 

  • Harley CB (2008) Telomerase and cancer therapeutics. Nat Rev Cancer 8(3):167–179

    Article  PubMed  CAS  Google Scholar 

  • Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460

    Article  PubMed  CAS  Google Scholar 

  • Hashizume R, Ozawa T, Gryaznov SM, Bollen AW, Lamborn KR, Frey WH, Deen DF (2008) New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163. Neuro Oncol 10:112–120

    Article  PubMed  CAS  Google Scholar 

  • Herbert BS, Gellert GC, Hochreiter A, Pongracz K, Wright WE, Zielinska D, Chin AC, Harley CB, Shay JW, Gryaznov SM (2005) Lipid modification of GRN163, an N3’–P5’ thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene 24:5262–5268

    Article  PubMed  CAS  Google Scholar 

  • Ho MM, Ng AV, Lam S, Hung JY (2007) Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 67:4827–4833

    Article  PubMed  CAS  Google Scholar 

  • Hochreiter AE, Xiao H, Goldblatt EM, Gryaznov SM, Miller KD, Badve S, Sledge GW, Herbert BS (2006) Telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth, and metastasis of breast cancer. Clin Cancer Res 12:3184–3192

    Article  PubMed  CAS  Google Scholar 

  • Jackson SR, Zhu CH, Paulson V, Watkins L, Dikmen ZG, Gryaznov SM, Wright WE, Shay JW (2007) Antiadhesive effects of GRN163L–an oligonucleotide N3’  > P5’ thio-phosphoramidate targeting telomerase. Cancer Res 67:1121–1129

    Article  PubMed  CAS  Google Scholar 

  • Jason TL, Koropatnick J, Berg RW (2004) Toxicology of antisense therapeutics. Toxicol Appl Pharmacol 201:66–83

    Article  PubMed  CAS  Google Scholar 

  • Koga S, Kondo Y, Komata T, Kondo S (2001) Treatment of bladder cancer cells in vitro and in vivo with 2–5A antisense telomerase RNA. Gene Ther 8:654–658

    Article  PubMed  CAS  Google Scholar 

  • Kondo S, Kondo Y, Li G, Silverman RH, Cowell JK (1998) Targeted therapy of human malignant glioma in a mouse model by 2–5A antisense directed against telomerase RNA. Oncogene 16: 3323–3330

    Article  PubMed  CAS  Google Scholar 

  • Kushner DM, Paranjape JM, Bandyopadhyay B, Cramer H, Leaman DW, Kennedy AW, Silverman RH, Cowell JK (2000) 2–5A antisense directed against telomerase RNA produces apoptosis in ovarian cancer cells. Gynecol Oncol 76: 183–192

    Article  PubMed  CAS  Google Scholar 

  • Kyo S, Takakura M, Fujiwara T, Inoue M (2008) Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. Cancer Sci 99:1528–1538

    Article  PubMed  CAS  Google Scholar 

  • Lebkowski JS, Gold J, Xu C, Funk W, Chiu CP, Carpenter MK (2001) Human embryonic stem cells: culture, differentiation, and genetic modification for regenerative medicine applications. Cancer J 7(Suppl 2):S83–S93

    PubMed  Google Scholar 

  • Ludwig A, Saretzki G, Holm PS, Tiemann F, Lorenz M, Emrich T, Harley CB, von Zglinicki T (2001) Ribozyme cleavage of telomerase mRNA sensitizes breast epithelial cells to inhibitors of topoisomerase. Cancer Res 61:3053–3061

    PubMed  CAS  Google Scholar 

  • Martens UM, Chavez EA, Poon SSS, Schmoor C, Lansdorp PM (2000) Accumulation of short telomeres in human fibroblasts prior to replicative senescence. Exp Cell Res 256:291–299

    Article  PubMed  CAS  Google Scholar 

  • McEachern MJ, Krauskopf A, Blackburn EH (2000) Telomeres and their control. Annu Rev Genet 34:331–358

    Article  PubMed  CAS  Google Scholar 

  • Melana SM, Holland JF, Pogo BG (1998) Inhibition of cell growth and telomerase activity of breast cancer cells in vitro by 3’-azido-3’-deoxythymidine. Clin Cancer Res 4:693–696

    PubMed  CAS  Google Scholar 

  • Mergny JL, Riou JF, Mailliet P, Teulade-Fichou MP, Gilson E (2002) Natural and pharmacological regulation of telomerase. Nucleic Acids Res 30:839–865

    Article  PubMed  CAS  Google Scholar 

  • Misawa M, Tauchi T, Sashida G, Nakajima A, Abe K, Ohyashiki JH, Ohyashiki K (2002) Inhibition of human telomerase enhances the effect of chemotherapeutic agents in lung cancer cells. Int J Oncol 21:1087–1092

    PubMed  CAS  Google Scholar 

  • Moyzis R, Buckingham J, Cram L, Dani M, Deaven L, Jones M, Meyene J, Ratliff R, Wu J-R (1988) A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A 85: 6622–6626

    Article  PubMed  CAS  Google Scholar 

  • Nakajima A, Tauchi T, Sashida G, Sumi M, Abe K, Yamamoto K, Ohyashiki JH, Ohyashiki K (2003) Telomerase inhibition enhances apoptosis in human acute leukemia cells: possibility of antitelomerase therapy. Leukemia 17:560–567

    Article  PubMed  CAS  Google Scholar 

  • Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277: 955–959

    Article  PubMed  CAS  Google Scholar 

  • Nosrati M, Li S, Bagheri S, Ginzinger D, Blackburn EH, Debs RJ, Kashani-Sabet M (2004) Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA. Clin Cancer Res 10:4983–4990

    Article  PubMed  CAS  Google Scholar 

  • Ohyashiki JH, Sashida G, Tauchi T, Ohyashiki K (2002) Telomeres and telomerase in hematologic neoplasia. Oncogene 21:680–687

    Article  PubMed  CAS  Google Scholar 

  • Olaussen KA, Dubrana K, Domont J, Spano JP, Sabatier L, Soria JC (2006) Telomeres and telomerase as targets for anticancer drug development. Crit Rev Oncol Hematol 57: 191–214

    Article  PubMed  Google Scholar 

  • Olovnikov AM (1973) A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41:181–190

    Article  PubMed  CAS  Google Scholar 

  • Oulton R, Harrington L (2000) Telomeres, telomerase, and cancer: life on the edge of genomic stability. Curr Opin Oncol 12:74–81

    Article  PubMed  CAS  Google Scholar 

  • Ozawa T, Gryaznov SM, Hu LJ, Pongracz K, Santos RA, Bollen AW, Lamborn KR, Deen DF (2004) Antitumor effects of specific telomerase inhibitor GRN163 in human glioblastoma xenografts. Neuro oncol 6:218–226

    Article  PubMed  CAS  Google Scholar 

  • Pascolo E, Wenz C, Lingner J, Hauel N, Priepke H, Kauffmann I, Garin-Chesa P, Rettig WJ, Damm K, Schnapp A (2002) Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate. J Biol Chem 277: 15566–15572

    Article  PubMed  CAS  Google Scholar 

  • Pendino F, Tarkanyi I, Dudognon C, Hillion J, Lanotte M, Aradi J, Segal-Bendirdjian E (2006) Telomeres and telomerase: pharmacological targets for new anticancer strategies? Curr Cancer Drug Targets 6:147–180

    Article  PubMed  CAS  Google Scholar 

  • Phatak P, Burger AM (2007) Telomerase and its potential for therapeutic intervention. Br J Pharmacol 152:1003–1011

    Article  PubMed  CAS  Google Scholar 

  • Phatak P, Cookson JC, Dai F, Smith V, Gartenhaus RB, Stevens MF, Burger AM (2007) Telomere uncapping by the G-quadruplex ligand RHPS4 inhibits clonogenic tumour cell growth in vitro and in vivo consistent with a cancer stem cell targeting mechanism. Br J Cancer 96:1223–1233

    Article  PubMed  CAS  Google Scholar 

  • Rankin AM, Faller DV, Spanjaard RA (2008) Telomerase inhibitors and ‘T-oligo’ as cancer therapeutics: contrasting molecular mechanisms of cytotoxicity. Anticancer Drugs 19:329–338

    Article  PubMed  CAS  Google Scholar 

  • Röth A, Baerlocher GM (2008) Dyskeratosis congenita. Br J Haematol 141:412

    Article  Google Scholar 

  • Röth A, Baerlocher GM, Schertzer M, Chavez E, Dührsen U, Lansdorp PM (2005) Telomere loss, senescence, and genetic instability in CD4+ T lymphocytes overexpressing hTERT. Blood 106: 43–50

    Article  PubMed  CAS  Google Scholar 

  • Röth A, de Beer D, Dürig J, Dührsen U, Elias L, Tressler R, Baerlocher GM (2008) Extremely short telomeres and high telomerase activity in T-cell prolymphocytic leukemia (T-PLL): An optimal target for telomerase inhibition with GRN163L? J Clin Oncol (Meeting Abstracts) 26:7061

    Google Scholar 

  • Röth A, Dürig J, Himmelreich H, Bug S, Siebert R, Dührsen U, Lansdorp PM, Baerlocher GM (2007) Short telomeres and high telomerase activity in T-cell prolymphocytic leukemia. Leukemia 21:2456–2462

    Article  PubMed  CAS  Google Scholar 

  • Röth A, Vercauteren S, Sutherland HJ, Lansdorp PM (2003a) Telomerase is limiting the growth of acute myeloid leukemia cells. Leukemia 17: 2410–2417

    Article  PubMed  CAS  Google Scholar 

  • Röth A, Yssel H, Pene J, Chavez EA, Schertzer M, Lansdorp PM, Spits H, Luiten RM (2003b) Telomerase levels control the lifespan of human T lymphocytes. Blood 102:849–857

    Article  PubMed  CAS  Google Scholar 

  • Rufer N, Dragowska W, Thornbury G, Roosnek E, Lansdorp PM (1998) Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat Biotechnol 16: 743–747

    Article  PubMed  CAS  Google Scholar 

  • Saretzki G, Ludwig A, von Zglinicki T, Runnebaum IB (2001) Ribozyme-mediated telomerase inhibition induces immediate cell loss but not telomere shortening in ovarian cancer cells. Cancer Gene Ther 8:827–834

    Article  PubMed  CAS  Google Scholar 

  • Shay JW, Wright WE (2002) Telomerase: a target for cancer therapeutics. Cancer Cell 2:257–265

    Article  PubMed  CAS  Google Scholar 

  • Smogorzewska A, de Lange T (2004) Regulation of telomerase by telomeric proteins. Annu Rev Biochem 73:177–208

    Article  PubMed  CAS  Google Scholar 

  • Strahl C, Blackburn EH (1996) Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in two immortalized human cell lines. Mol Cell Biol 16:53–65

    PubMed  CAS  Google Scholar 

  • Tauchi T, Nakajima A, Sashida G, Shimamoto T, Ohyashiki JH, Abe K, Yamamoto K, Ohyashiki K (2002) Inhibition of human telomerase enhances the effect of the tyrosine kinase inhibitor, imatinib, in BCR-ABL-positive leukemia cells. Clin Cancer Res 8:3341–3347

    PubMed  CAS  Google Scholar 

  • Tauchi T, Shin-ya K, Sashida G, Sumi M, Nakajima A, Shimamoto T, Ohyashiki JH, Ohyashiki K (2003) Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways. Oncogene 22:5338–5347

    Article  PubMed  CAS  Google Scholar 

  • Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, Cohen D, Harley CB (1993) Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 52:661–667

    PubMed  CAS  Google Scholar 

  • Verfaillie CM, Pera MF, Lansdorp PM (2002) Stem cells: hype and reality. Hematol Am Soc Hematol Educ Program 369–391

    Google Scholar 

  • Vulliamy T, Beswick R, Kirwan M, Marrone A, Digweed M, Walne A, Dokal I (2008) Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci U S A 105: 8073–8078

    Article  PubMed  Google Scholar 

  • Walne AJ, Vulliamy T, Marrone A, Beswick R, Kirwan M, Masunari Y, Al Qurashi FH, Aljurf M, Dokal I (2007) Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet 16:1619–1629

    Article  PubMed  CAS  Google Scholar 

  • Wang ES, Wu K, Chin AC, Chen-Kiang S, Pongracz K, Gryaznov S, Moore MA (2004) Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma. Blood 103:258–266

    Article  PubMed  CAS  Google Scholar 

  • Ward RJ, Autexier C (2005) Pharmacological telomerase inhibition can sensitize drug-resistant and drug-sensitive cells to chemotherapeutic treatment. Mol Pharmacol 68:779–786

    PubMed  CAS  Google Scholar 

  • Watson JD (1972) Origin of concatameric T4 DNA. Nat New Biol 239:197–201

    Article  PubMed  CAS  Google Scholar 

  • Weng NP, Granger L, Hodes RJ (1997) Telomere lengthening and telomerase activation during human B cell differentiation. Proc Natl Acad Sci U S A 94:10827–10832

    Article  PubMed  CAS  Google Scholar 

  • Wong KK, Chang S, Weiler SR, Ganesan S, Chaudhuri J, Zhu C, Artandi SE, Rudolph KL, Gottlieb GJ, Chin L, Alt FW, DePinho RA (2000) Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nat Genet 26:85–88

    Article  PubMed  CAS  Google Scholar 

  • Yatabe N, Kyo S, Kondo S, Kanaya T, Wang Z, Maida Y, Takakura M, Nakamura M, Tanaka M, Inoue M (2002) 2–5A antisense therapy directed against human telomerase RNA inhibits telomerase activity and induces apoptosis without telomere impairment in cervical cancer cells. Cancer Gene Ther 9:624–630

    Article  PubMed  CAS  Google Scholar 

  • Yeo M, Rha SY, Jeung HC, Hu SX, Yang SH, Kim YS, An SW, Chung HC (2005) Attenuation of telomerase activity by hammerhead ribozyme targeting human telomerase RNA induces growth retardation and apoptosis in human breast tumor cells. Int J Cancer 114:484–489

    Article  PubMed  CAS  Google Scholar 

  • Yokoyama Y, Takahashi Y, Shinohara A, Lian Z, Wan X, Niwa K, Tamaya T (1998) Attenuation of telomerase activity by a hammerhead ribozyme targeting the template region of telomerase RNA in endometrial carcinoma cells. Cancer Res 58: 5406–5410

    PubMed  CAS  Google Scholar 

  • Yokoyama Y, Takahashi Y, Shinohara A, Wan X, Takahashi S, Niwa K, Tamaya T (2000) The 5’-end of hTERT mRNA is a good target for hammerhead ribozyme to suppress telomerase activity. Biochem Biophys Res Commun 273: 316–321

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Mar V, Zhou W, Harrington L, Robinson MO (1999) Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev 13:2388–2399

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122, Essen, Germany

    Alexander Röth

Authors
  1. Alexander Röth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Calvin B. Harley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gabriela M. Baerlocher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander Röth .

Editor information

Editors and Affiliations

  1. Medizinische Klinik III, SLK-Kliniken Heilbronn GmbH, Am Gesundbrunen 20-26, Heilbronn, 74078, Germany

    Uwe M. Martens

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Röth, A., Harley, C.B., Baerlocher, G.M. (2010). Imetelstat (GRN163L) - Telomerase-Based Cancer Therapy. In: Martens, U. (eds) Small Molecules in Oncology. Recent Results in Cancer Research, vol 184. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-01222-8_16

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-01222-8_16

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-01221-1

  • Online ISBN: 978-3-642-01222-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation