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Vol. 292, Issue 3, 921-928, March 2000
AVI BioPharma, Corvallis, Oregon (V.A., D.C.K., M.L.S., D.A.S.,
M.T.R., D.D.W., P.L.I.), and Laboratory Animal Resources, Oregon State
University, Corvallis, Oregon (B.L.S.)
Expression of c-myc protein is associated with cell proliferation. The
present study uses antisense oligomers to inhibit c-myc expression 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.
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