Telomerase inhibition with an oligonucleotide telomerase template antagonist: In vitro and in vivo studies in multiple myeloma and lymphoma Journal Article

Authors: Wang, E. S.; Wu, K.; Chin, A. C.; Chen-Kiang, S.; Pongracz, K.; Gryaznov, S.; Moore, M. A. S.
Article Title: Telomerase inhibition with an oligonucleotide telomerase template antagonist: In vitro and in vivo studies in multiple myeloma and lymphoma
Abstract: The effects of telomerase inhibition with an oligonucleotide N3′ → P5′ thiophosphoramidate (GRN163) complementary to the telomerase template region were examined on human multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) cell lines, primary MM cells, and tumor xenografts. GRN163 treatment reduced telomerase levels in all cells and induced more rapid telomeric shortening. Continuous GRN163 treatment for 7 to 14 days resulted in proliferative arrest, morphologic changes, and apoptosis characteristic of cell crisis in tumor cell lines with short (1.7-5.4 kb) but not long (9-11 kb) telomeres. Intratumoral administration of GRN163 also inhibited the growth of MM and NHL xenografts established from cell lines with short telomeres (Hs602 lymphoma, 2.7 kb; CAG myeloma, 2.7 kb) and increased tumor apoptosis. However, GRN163 therapy of NHL xenografts established from cells with long telomeres (11.0 kb) had equivocal effects on tumor growth and did not induce apoptosis during this time frame. Systemic daily intraperitoneal administration of GRN163 in myeloma xenografts with short telomere lengths also decreased tumor telomerase levels and reduced tumor volumes. These data demonstrate that telomerase is important for the replication of mature B-cell neoplasia by stabilizing short telomeres, and they suggest that telomerase inhibition represents a novel therapeutic approach to MM and NHL. © 2004 by The American Society of Hematology.
Keywords: human cell; telomere; animals; mice; cell death; cell division; apoptosis; enzyme inhibition; multiple myeloma; tumor volume; continuous infusion; tumor xenograft; mice, scid; enzyme activity; cell line, tumor; telomerase; lymphoma, non-hodgkin; lymphoma; transplantation, heterologous; base sequence; neoplasm transplantation; tumor growth; mice, inbred nod; oligonucleotide; oligodeoxyribonucleotides, antisense; genetic complementation; receptor upregulation; oncogene n ras; cell immortalization; b lymphocyte activation; oligonucleotide probe; humans; human; priority journal; article; phosphorothioic acid derivative
Journal Title: Blood
Volume: 103
Issue: 1
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2004-01-01
Start Page: 258
End Page: 266
Language: English
DOI: 10.1182/blood-2003-02-0546
PROVIDER: scopus
PUBMED: 12969977
Notes: Blood -- Cited By (since 1996):54 -- Export Date: 16 June 2014 -- CODEN: BLOOA -- Source: Scopus
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MSK Authors
  1. Kaida Wu
    29 Wu
  2. Eunice S Wang
    13 Wang
  3. Malcolm A S Moore
    427 Moore