© 2004 by Society
© 2004 by the Society forNeuro-Oncology
Antitumor effects of specific telomerase inhibitor GRN163 in humanglioblastoma xenografts
Brain Tumor Research Center of the Department ofNeurological Surgery (T.O., L.J.H., R.A.S., K.R.L., D.F.D.) and Department of Pathology (A.W.B.), University of CaliforniaSan Francisco, San Francisco, CA 94143-0520; and GeronCorporation, Menlo Park, CA 94025 (S.M.G., K.P.); USA
2 Address correspondence to Dennis F. Deen, Brain Tumor Research Center, 505Parnassus Ave., U-378, University of California San Francisco, San Francisco,CA 94143-0520, USA(ddeen{at}itsa.ucsf.edu).
 |
Abstract |
|---|
Telomerase is a ribonucleoprotein complex that elongates telomeric DNA andappears to play an important role in cellular immortalization of cancers.Because telomerase is expressed in the vast majority of malignant gliomas butnot in normal brain tissues, it is a logical target for glioma-specifictherapy. The telomerase inhibitor GRN163, a 13-mer oligonucleotideN3'
P5' thio-phosphoramidate (Geron Corporation,Menlo Park, Calif.), is complementary to the template region of the humantelomerase RNA subunit hTR. When athymic mice bearing U-251 MG human braintumor xenografts in their flanks were treated intratumorally with GRN163, asignificant growth delay in tumor size was observed (P < 0.01 inall groups) as compared to the tumor size in mice receiving a mismatchedoligonucleotide or the carrier alone. We also investigated biodistribution ofthe drug in vivo in an intracerebral rat brain-tumor model.Fluorescein-labeled GRN163 was loaded into an osmotic minipump and infuseddirectly into U-251 MG brain tumors over 7 days. Examination of the brainsrevealed that GRN163 was present in tumor cells at all time points studied.When GRN163 was infused into intracerebral U-251 MG tumors shortly after theirimplantation, it prevented their establishment and growth. Lastly, when ratswith larger intracerebral tumors were treated with the inhibitor, GRN163increased animal survival times. Our results demonstrate that theantitelomerase agent GRN163 inhibits growth of glioblastoma in vivo, exhibitsfavorable intracerebral tumor uptake properties, and prevents the growth ofintracerebral tumors. These findings support further development of thiscompound as a potential anticancer agent.
Received January 16, 2004; Accepted March 30, 2004
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. Hashizume, T. Ozawa, S. M. Gryaznov, A. W. Bollen, K. R. Lamborn, W. H. Frey II, and D. F. Deen New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163 Neuro Oncology, April 1, 2008; 10(2): 112 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Jackson, C.-H. Zhu, V. Paulson, L. Watkins, Z. G. Dikmen, S. M. Gryaznov, W. E. Wright, and J. W. Shay Antiadhesive Effects of GRN163L--An Oligonucleotide N3'->P5' Thio-Phosphoramidate Targeting Telomerase Cancer Res., February 1, 2007; 67(3): 1121 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Hochreiter, H. Xiao, E. M. Goldblatt, S. M. Gryaznov, K. D. Miller, S. Badve, G. W. Sledge, and B.-S. Herbert Telomerase Template Antagonist GRN163L Disrupts Telomere Maintenance, Tumor Growth, and Metastasis of Breast Cancer. Clin. Cancer Res., May 15, 2006; 12(10): 3184 - 3192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. G. Dikmen, G. C. Gellert, S. Jackson, S. Gryaznov, R. Tressler, P. Dogan, W. E. Wright, and J. W. Shay In vivo Inhibition of Lung Cancer by GRN163L: A Novel Human Telomerase Inhibitor Cancer Res., September 1, 2005; 65(17): 7866 - 7873. [Abstract] [Full Text] [PDF]
|
|