JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zellweger, T.
Right arrow Articles by Gleave, M. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zellweger, T.
Right arrow Articles by Gleave, M. E.

Vol. 298, Issue 3, 934-940, September 2001

Antitumor Activity of Antisense Clusterin Oligonucleotides Is Improved in Vitro and in Vivo by Incorporation of 2'-O-(2-Methoxy)Ethyl Chemistry

Tobias Zellweger, Hideaki Miyake, Scott Cooper, Kim Chi, Boyd S. Conklin, Brett P. Monia and Martin E. Gleave

The Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia, Canada (T.Z., H.M., K.C., M.E.G.); and ISIS Pharmaceuticals, Carlsbad, California (S.C., B.S.C., B.P.M.)

Phosphorothioate (P=S) antisense oligonucleotides (ASO) targeting the cell survival gene clusterin synergistically enhance castration- and chemotherapy-induced apoptosis in prostate cancer xenografts. This study compares efficacy, tissue half-lives, and toxicity of P=S clusterin ASO to third-generation backbone 2'-O-(2-methoxy)ethyl (2'MOE) ribose-modified clusterin ASO. Northern analysis quantified changes in clusterin mRNA levels in human PC-3 cells and tumors. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay measured effects of combined clusterin ASO plus paclitaxel on PC-3 cell growth. Athymic mice bearing PC-3 tumors were treated with paclitaxel plus either P=S clusterin ASO, 2'-MOE clusterin ASO, or mismatch control oligonucleotides for 28 days. Weekly body weights and serum parameters were measured to assess toxicity. Tissue half-life of P=S and 2'-MOE ASO in PC-3 tumors was assessed using capillary gel electrophoresis (CGE). Both 2'-MOE and P=S ASO decreased clusterin mRNA levels in a dose-dependent and sequence-specific manner. 2'-MOE ASO more potently suppressed clusterin mRNA (80 versus 40% at 500 nM) compared with P=S ASO. IC50 of paclitaxel was equally reduced (50-75%) by both compounds. In vivo tissue half-life was significantly longer for 2'-MOE-modified ASO than for P=S ASO (5 versus 0.5 days). Using CGE, >90% of detected 2'-MOE ASO in tumor tissue was full length. Weekly administration of 2'-MOE clusterin ASO was equivalent to daily P=S clusterin ASO in enhancing paclitaxel efficacy in vivo. 2'-MOE-modified ASO potently suppressed clusterin expression and prolonged tissue half-lives with no additional side effects. These results support the use of 2'-MOE-modified ASO over conventional P=S ASO by potentially increasing potency and allowing longer dosing intervals in clinical trials.

0022-3565/01/2983-0934$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
K. N. Chi, L. L. Siu, H. Hirte, S. J. Hotte, J. Knox, C. Kollmansberger, M. Gleave, E. Guns, J. Powers, W. Walsh, et al.
A Phase I Study of OGX-011, a 2'-Methoxyethyl Phosphorothioate Antisense to Clusterin, in Combination with Docetaxel in Patients with Advanced Cancer
Clin. Cancer Res., February 1, 2008; 14(3): 833 - 839.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
S. Davis, B. Lollo, S. Freier, and C. Esau
Improved targeting of miRNA with antisense oligonucleotides.
Nucleic Acids Res., January 1, 2006; 34(8): 2294 - 2304.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
P. Rocchi, E. Beraldi, S. Ettinger, L. Fazli, R. L. Vessella, C. Nelson, and M. Gleave
Increased Hsp27 after Androgen Ablation Facilitates Androgen-Independent Progression in Prostate Cancer via Signal Transducers and Activators of Transcription 3-Mediated Suppression of Apoptosis
Cancer Res., December 1, 2005; 65(23): 11083 - 11093.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
A. So, S. Sinnemann, D. Huntsman, L. Fazli, and M. Gleave
Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo
Mol. Cancer Ther., December 1, 2005; 4(12): 1837 - 1849.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
K. N. Chi, E. Eisenhauer, L. Fazli, E. C. Jones, S. L. Goldenberg, J. Powers, D. Tu, and M. E. Gleave
A Phase I Pharmacokinetic and Pharmacodynamic Study of OGX-011, a 2'-Methoxyethyl Antisense Oligonucleotide to Clusterin, in Patients With Localized Prostate Cancer
J Natl Cancer Inst, September 7, 2005; 97(17): 1287 - 1296.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
A. A. Adjei and M. Hidalgo
Intracellular Signal Transduction Pathway Proteins As Targets for Cancer Therapy
J. Clin. Oncol., August 10, 2005; 23(23): 5386 - 5403.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. Stankova, J. Shang, and R. Rozen
Antisense Inhibition of Methylenetetrahydrofolate Reductase Reduces Cancer Cell Survival In vitro and Tumor Growth In vivo
Clin. Cancer Res., March 1, 2005; 11(5): 2047 - 2052.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
K. Yamanaka, M. E. Gleave, I. Hara, M. Muramaki, and H. Miyake
Synergistic antitumor effect of combined use of adenoviral-mediated p53 gene transfer and antisense oligodeoxynucleotide targeting clusterin gene in an androgen-independent human prostate cancer model
Mol. Cancer Ther., February 1, 2005; 4(2): 187 - 195.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
I. P. Trougakos, A. So, B. Jansen, M. E. Gleave, and E. S. Gonos
Silencing Expression of the Clusterin/Apolipoprotein J Gene in Human Cancer Cells Using Small Interfering RNA Induces Spontaneous Apoptosis, Reduced Growth Ability, and Cell Sensitization to Genotoxic and Oxidative Stress
Cancer Res., March 1, 2004; 64(5): 1834 - 1842.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Kiyama, K. Morrison, T. Zellweger, M. Akbari, M. Cox, D. Yu, H. Miyake, and M. E. Gleave
Castration-Induced Increases in Insulin-Like Growth Factor-Binding Protein 2 Promotes Proliferation of Androgen-independent Human Prostate LNCaP Tumors
Cancer Res., July 1, 2003; 63(13): 3575 - 3584.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. Urban, T. Golden, I. V. Aragon, L. Cowsert, S. R. Cooper, N. M. Dean, and R. E. Honkanen
Identification of a Functional Link for the p53 Tumor Suppressor Protein in Dexamethasone-induced Growth Suppression
J. Biol. Chem., March 7, 2003; 278(11): 9747 - 9753.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. Zellweger, K. Chi, H. Miyake, H. Adomat, S. Kiyama, K. Skov, and M. E. Gleave
Enhanced Radiation Sensitivity in Prostate Cancer by Inhibition of the Cell Survival Protein Clusterin
Clin. Cancer Res., October 1, 2002; 8(10): 3276 - 3284.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics.