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© 1995 American Heart Association, Inc.
Articles |
c-myc in Vasculoproliferative Disease
From Harvard University–Massachusetts Institute of Technology, Division of Health Sciences and Technology (E.R.E.), Cambridge; the Department of Medicine (E.R.E., M.S., R.D.R.), Harvard Medical School, Boston, Mass; and the Department of Biology (M.S., M.G.S., R.D.R.), Massachusetts Institute of Technology, Cambridge.
Abstract Antisense oligonucleotides to genes central to cellular proliferation have suppressed smooth muscle cell growth in vitro and in vivo. We now report that although the response of cultured smooth muscle cells to antisense oligonucleotides to c-myc and c-myb is identical, the response of the injured arterial wall to these oligomers depends on the kinetics of gene expression and oligonucleotide delivery. Two different antisense oligonucleotides to each oncogene were administered to the perivascular aspect of injured rat carotid arteries via polymer-based delivery systems. The acute release of antisense oligonucleotides from the Pluronic gels reduced in vitro cell growth 54.8% with c-myc and 56.9% with c-myb. The more sustained release from ethylene vinyl acetate copolymer (EVAc) matrices was slightly less efficient, inhibiting proliferation 47.3% and 43.3%, respectively. However, although both EVAc and Pluronic release of c-myb antisense oligonucleotide sequences inhibited intimal hyperplasia 2 weeks after injury, only the more prolonged EVAc matrix release of antisense oligonucleotide to c-myc was effective. The failure of the short course of c-myc oligomer release from Pluronic gels stemmed from early successful suppression with late loss of regulation and not from inactivation of the antisense oligonucleotide within the polymeric gel. Within 24 hours of injury, Pluronic-based release of c-myc antisense oligomers reduced mRNA levels in the tunica media 2.5-fold and immunocytochemical identification of c-myc expression by 98.8%. As a result, the number of proliferating cells was decreased 6.5-fold 3 days after injury. One week after injury, however, the effect of Pluronic gel–released c-myc antisense was lost on both the number of cells expressing the oncogene (only 29.6% suppression) and the extent of intimal hyperplasia (intimal-to-medial area ratio, 0.35±0.02 versus 0.5±0.1 in control arteries). In contrast, EVAc release of the same sequences obliterated protein expression, maintaining a 99.6±0.7% inhibition for the duration of the experiment, and reduced intimal hyperplasia 2 weeks after injury 11.1-fold. We conclude that the effectiveness of the antisense approach to suppression of neointimal proliferation depends on the time course of expression of the target gene as well as the kinetics of oligonucleotide delivery.
Key Words: antisense oligonucleotides • c-myb • c-myc • restenosis • polymer-based drug delivery
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