793-4 Local Delivery of C-myb Antisense attenuates Neo-Intimal Thickening in a Porcine Model of Coronary Angioplasty
Identifieur interne : 002C50 ( Main/Merge ); précédent : 002C49; suivant : 002C51793-4 Local Delivery of C-myb Antisense attenuates Neo-Intimal Thickening in a Porcine Model of Coronary Angioplasty
Auteurs : Julian Gunn [Royaume-Uni] ; Cathy M. Holt [Royaume-Uni] ; Lynda Shepherd [Royaume-Uni] ; Sheila E. Francis [Royaume-Uni] ; Geoffrey H. Smith [Royaume-Uni] ; David C. Cumberland [Royaume-Uni]Source :
- Journal of the American College of Cardiology [ 0735-1097 ] ; 1995.
English descriptors
- Teeft :
- Acei, Angioplasty, Antisense, Arterial gene transfer, Balloon angioplasty, Balloon injury, Baseline, Cardiac surgery, Chloroquine, Complete repair, Diameter stenosis, Enoxaparin, Enzyme inhibition, Exercise capacity, Gene transfer, Heparin, Local delivery, Morial convention center, Nitrosated albumin, Pcna, Percutaneous, Platelet, Platelet adhesion, Platelet deposition, Porcine, Porcine model, Pregnancy, Pressure heparin delivery, Restenosis, Sham, Smooth muscle cell proliferation, Stenosed, Stenosis, Systemic treatment, Twin pregnancy, Unsuccessful pregnancies.
Abstract
Intimal smooth muscle cell proliferation and extracellular matrix production compose the restenotic lesion. The proto-oncogene c-myb is up-regulated in proliferating cells and is a common downstream link in several mitogenic pathways. We have recently shown that c-myb antisense specifically inhibits proliferation of several types of human vascular cells in vitro. The development of catheter-based local drug delivery systems allows us to test the feasibility and efficacy of local intra-mural delivery of c-myb antisense in a porcine model of coronary angioplasty.We first tested an unmodified HPLC-purified 18-mer antisense oligonucleotide directed against the human sequence of c-myb in porcine aortic smooth muscle cells in culture. More than 90% inhibition of cellular proliferation was observed at 5 M with no adverse effect on cellular viability. This effect was not seen with sense oligonucleotides.The in vivo delivery system used was the Transport (CVD) double skinned balloon catheter, allowing high pressure oversized balloon dilatation followed by low pressure delivery of 500 g antisense in 2 ml saline over 12mins. Ex vivo and in vivo delivery of fluorescein labelled oligonucleotide using this system demonstrated successful intramural localisation. Wethen performed oligo delivery in vivo into a single porcine coronary artery (n=10); the control group underwent angioplasty using a conventional balloon without drug delivery (n=12). Animals were sacrificed at 4 weeks. Quantitative morphometric analysis of serial transverse histological sections demonstrated a consistent reduction in absolute and percent intimal thicknesses and areas together with a significant reduction in mean (SEM) intimal/medial thickness ratio from 0.37 (0.09) to 0.13 (0.03) (p<0.05) in the treatment group.
Url:
DOI: 10.1016/0735-1097(95)93020-D
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Holt</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Sections of Cardiac Surgery and Cardiology, University of Sheffield, Northern General Hospital, Sheffield</wicri:regionArea><wicri:noRegion>Sheffield</wicri:noRegion></affiliation></author><author><name sortKey="Shepherd, Lynda" sort="Shepherd, Lynda" uniqKey="Shepherd L" first="Lynda" last="Shepherd">Lynda Shepherd</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Sections of Cardiac Surgery and Cardiology, University of Sheffield, Northern General Hospital, Sheffield</wicri:regionArea><wicri:noRegion>Sheffield</wicri:noRegion></affiliation></author><author><name sortKey="Francis, Sheila E" sort="Francis, Sheila E" uniqKey="Francis S" first="Sheila E." last="Francis">Sheila E. 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The proto-oncogene c-myb is up-regulated in proliferating cells and is a common downstream link in several mitogenic pathways. We have recently shown that c-myb antisense specifically inhibits proliferation of several types of human vascular cells in vitro. The development of catheter-based local drug delivery systems allows us to test the feasibility and efficacy of local intra-mural delivery of c-myb antisense in a porcine model of coronary angioplasty.We first tested an unmodified HPLC-purified 18-mer antisense oligonucleotide directed against the human sequence of c-myb in porcine aortic smooth muscle cells in culture. More than 90% inhibition of cellular proliferation was observed at 5 M with no adverse effect on cellular viability. This effect was not seen with sense oligonucleotides.The in vivo delivery system used was the Transport (CVD) double skinned balloon catheter, allowing high pressure oversized balloon dilatation followed by low pressure delivery of 500 g antisense in 2 ml saline over 12mins. Ex vivo and in vivo delivery of fluorescein labelled oligonucleotide using this system demonstrated successful intramural localisation. Wethen performed oligo delivery in vivo into a single porcine coronary artery (n=10); the control group underwent angioplasty using a conventional balloon without drug delivery (n=12). Animals were sacrificed at 4 weeks. Quantitative morphometric analysis of serial transverse histological sections demonstrated a consistent reduction in absolute and percent intimal thicknesses and areas together with a significant reduction in mean (SEM) intimal/medial thickness ratio from 0.37 (0.09) to 0.13 (0.03) (p<0.05) in the treatment group.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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