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Research ArticleArticle

Antisense Oligonucleotides Targeted to thep53 Gene Modulate Liver Regeneration In Vivo

Vikram Arora and Patrick L. Iversen
Drug Metabolism and Disposition February 2000, 28 (2) 131-138;
Vikram Arora
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Patrick L. Iversen
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Abstract

The rapidly proliferating cells of the regenerating liver after partial hepatectomy (PH) present a reproducible in vivo model to study the functional role of the tumor suppressor gene p53. The present study uses the rat 70% PH model along with systemic administration of three different structural types of antisense oligonucleotides (ODNs) designed to suppress p53 expression. We tested the hypothesis that antisense ODNs can inhibit the expression of p53, resulting in the loss of the G1-S cell cycle checkpoint and an altered pattern of liver regeneration. Intraperitoneal administration of 5 mg/kg/day antisense phosphorothioate ODN after 70% PH resulted in reduced expression of the p53 protein in the regenerating liver. There were concomitant increases in weight gain of remnant-regenerating liver and expression of proliferating cell nuclear antigen and p21waf-1 compared with either saline or 5 mg/kg/day mispaired phosphorothioate ODN treatment. Flow cytometric analysis of DNA content of isolated hepatocytes revealed a reduction in the G0/G1 cell population and accumulation of cells with more than 4n DNA in antisense-treated rats. The regenerating livers had significantly diminished cytochrome P-450 (CYP) enzyme activities. Rats treated with p53 antisense ODNs, but not saline or mispair ODN controls, had significantly elevated CYP activities. These observations functionally link the expression of p53 with diminished expression of several CYP isoforms in the liver regeneration model.

Footnotes

  • Send reprint requests to: Dr. Patrick L. Iversen, AVI Biopharma, Inc., 4575 S.W. Research Way, Suite 200, Corvallis, OR 97333. E-mail: piversen{at}avibio.com

  • This study was supported in part by USPHS Grant GM54871. V.A. received fellowship support from Nebraska Research Initiative in Biotechnology.

  • 1 Present address: AVI Biopharma, 4575 S.W. Research Way, Suite 200, Corvallis, OR 97333.

  • Abbreviations used are::
    PH
    partial hepatectomy
    ODN
    oligodeoxynucleotide
    PS-ODN
    phosphorothioate ODN
    C-5-P
    cytosine C-5 propynyl
    PCNA
    proliferating cell nuclear antigen
    MI
    mitotic index
    CYP
    cytochrome P-450
    TBARS
    thiobarbituric acid-reactive substances
    rcf
    relative centrifugal force
    • Received June 10, 1999.
    • Accepted October 12, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (2)
Drug Metabolism and Disposition
Vol. 28, Issue 2
1 Feb 2000
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Research ArticleArticle

Antisense Oligonucleotides Targeted to thep53 Gene Modulate Liver Regeneration In Vivo

Vikram Arora and Patrick L. Iversen
Drug Metabolism and Disposition February 1, 2000, 28 (2) 131-138;

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Research ArticleArticle

Antisense Oligonucleotides Targeted to thep53 Gene Modulate Liver Regeneration In Vivo

Vikram Arora and Patrick L. Iversen
Drug Metabolism and Disposition February 1, 2000, 28 (2) 131-138;
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