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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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
Journal of Pharmacology and Experimental Therapeutics September 2001, 298 (3) 934-940;
Tobias Zellweger
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Hideaki Miyake
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Scott Cooper
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Kim Chi
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Boyd S. Conklin
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Brett P. Monia
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Martin E. Gleave
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Abstract

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.

Footnotes

  • This work was supported in part by a grant from the Prostate Cancer Research Foundation of Canada, and the Hudson Fund at Vancouver Hospital. T.Z. was supported by the Swiss National Science Foundation, Krebsliga Basel, Lichtenstein-Stiftung, and Freiwillige Akademische Gesellschaft of the University of Basel, Switzerland.

  • Abbreviations:
    ASO
    antisense oligonucleotide
    P=O
    phosphodiester
    P=S
    phosphorothioate
    2′-MOE
    2′-O-(2-methoxy)ethyl
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    CGE
    capillary gel electrophoresis
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    • Received February 19, 2001.
    • Accepted May 11, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 3
1 Sep 2001
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 934-940;

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 934-940;
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