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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

c-Myc Antisense Limits Rat Liver Regeneration and Indicates Role for c-Myc in Regulating Cytochrome P-450 3A Activity

Vikram Arora, Derek C. Knapp, Barbara L. Smith, Mary L. Statdfield, David A. Stein, Muralimohan T. Reddy, Dwight D. Weller and Patrick L. Iversen
Journal of Pharmacology and Experimental Therapeutics March 2000, 292 (3) 921-928;
Vikram Arora
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Derek C. Knapp
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Barbara L. Smith
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Mary L. Statdfield
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David A. Stein
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Muralimohan T. Reddy
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Dwight D. Weller
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Patrick L. Iversen
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Abstract

Expression of c-myc protein is associated with cell proliferation. The present study uses antisense oligomers to inhibit c-mycexpression in the regenerating rat liver after 70% partial hepatectomy (PH). Antisense phosphorodiamidate morpholino oligomers (novel DNA analogs) were administered i.p. immediately after surgery to block expression of c-myc within the first 24 h after PH. A 20-mer PMO complimentary to the c-myc mRNA at the translation start site was an effective sequence (AVI-4126, 5′-ACGTTGAGGGGCATCGTCGC-3′). A single i.p. dose of 0.5 mg/kg AVI-4126 caused reduction of the regenerating liver c-myc protein in a sequence-specific and dose-dependent manner. Inhibition of c-myc expression resulted in reduction of proliferating cell nuclear antigen and arrested cells in the G0/G1 phase of the cell cycle. The ratio of G2:G0 cell populations in the regenerating liver 24 h after PH dropped from 29.1 in saline vehicle-treated rats to 18.0 in rats treated with 2.5 mg/kg AVI-4126. The expression of cell cycle checkpoint protein p53 was inhibited with increasing doses of AVI-4126, but expression of p21waf-1 was unaffected. The activity of cytochrome P-450 3A2 (CYP3A2) was evaluated by immunoblot analysis and erythromycin N-demethylation. AVI-4126 did not alter CYP3A activity in nonhepatectamized animals but showed a dose-dependent decrease in PH rats. We conclude that AVI-4126, antisense oligomer to c-myc, can reduce cell proliferation in the regenerating rat liver. Furthermore, inhibition of c-myc may indirectly influence the expression of CYP3A.

Footnotes

  • Send reprint requests to: Patrick L. Iversen, Ph.D., AVI BioPharma, 4575 SW Research Way, Suite 200, Corvallis, OR 97333. E-mail: piversen{at}avibio.com

  • ↵1 This study was supported by funds from AVI Biopharma and U.S. Public Health Service Grant GM54871.

  • Abbreviations:
    PH
    partial hepatectomy
    PMO
    phosphorodiamidate morpholino oligomer
    CYP
    cytochrome P-450
    PCNA
    proliferating cell nuclear antigen
    cdk
    cyclin dependent kinase
    • Received September 28, 1999.
    • Accepted December 1, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 3
1 Mar 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

c-Myc Antisense Limits Rat Liver Regeneration and Indicates Role for c-Myc in Regulating Cytochrome P-450 3A Activity

Vikram Arora, Derek C. Knapp, Barbara L. Smith, Mary L. Statdfield, David A. Stein, Muralimohan T. Reddy, Dwight D. Weller and Patrick L. Iversen
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 921-928;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

c-Myc Antisense Limits Rat Liver Regeneration and Indicates Role for c-Myc in Regulating Cytochrome P-450 3A Activity

Vikram Arora, Derek C. Knapp, Barbara L. Smith, Mary L. Statdfield, David A. Stein, Muralimohan T. Reddy, Dwight D. Weller and Patrick L. Iversen
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 921-928;
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