Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma.
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.
Wang
Eunice S
ES
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Wu
Kaida
K
Chin
Allison C
AC
Chen-Kiang
Selina
S
Pongracz
Krisztina
K
Gryaznov
Sergei
S
Moore
Malcolm A S
MA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D066298:In Vitro Techniques; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D009368:Neoplasm Transplantation; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016615:Telomere / Q000187:drug effects / Q000473:pathology; D014183:Transplantation, Heterologous
D020319:Oligodeoxyribonucleotides, Antisense; D019098:Telomerase