TY - JOUR
T1 - In vivo inhibition of lung cancer by GRN163L
T2 - A novel human telomerase inhibitor
AU - Dikmen, Z. Gunnur
AU - Gellert, Ginelle C.
AU - Jackson, Shalmica
AU - Gryaznov, Sergei
AU - Tressler, Robert
AU - Dogan, Pakize
AU - Wright, Woodring E.
AU - Shay, Jerry W.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/9/1
Y1 - 2005/9/1
N2 - 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′-thiophosphoramidate, 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 μmol/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.
AB - 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′-thiophosphoramidate, 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 μmol/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.
UR - http://www.scopus.com/inward/record.url?scp=24744446474&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=24744446474&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-05-1215
DO - 10.1158/0008-5472.CAN-05-1215
M3 - Article
C2 - 16140956
AN - SCOPUS:24744446474
VL - 65
SP - 7866
EP - 7873
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 17
ER -