Gene Therapy Enhances the Antiproliferative Effect of Radiation in Intimal Hyperplasia

Background. Although ionizing radiation (IR) has been demonstrated to attenuate vessel wall restenosis and intimal hyperplasia (IH), dose-related mural injury and atrophy are possible deleterious side effects. We tested the hypothesis that a radiosensitizing strategy may improve IR-induced inhibitio...

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Published in:	The Journal of surgical research Vol. 89; no. 2; pp. 155 - 162
Main Authors:	Fortunato, John E., Mauceri, Helena J., Kocharyan, Hrachya, Song, Ruo H., Salloum, Rabih, Vosicky, James, Swedberg, Kirsten, Malik, Saira, Abusharif, Faris, Glagov, Seymour, Weichselbaum, Ralph R., Bassiouny, Hisham S.
Format:	Journal Article
Language:	English
Published:	New York, NY Elsevier Inc 01-04-2000 Elsevier
Subjects:	5-fluorocytosine 5-fluorouracil Animals Apoptosis - drug effects Apoptosis - radiation effects Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cardiovascular system Carotid Artery, Common - drug effects Carotid Artery, Common - pathology Carotid Artery, Common - physiopathology Cell Division - drug effects Cell Division - radiation effects Cytosine Deaminase Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Flucytosine - pharmacology Genetic Therapy Hemodynamics - drug effects Hemodynamics - radiation effects Hyperplasia - pathology intimal hyperplasia intimal/medial ionizing radiation Male Medical sciences Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - pathology Muscle, Smooth, Vascular - physiopathology Nucleoside Deaminases - genetics Pharmacology. Drug treatments Prodrugs - pharmacology proliferating cell nuclear antigen Rabbits right common carotid artery Tunica Intima - drug effects Tunica Intima - pathology Tunica Intima - radiation effects vascular smooth muscle cells Vascular wall 5-fluorouracil proliferating cell nuclear antigen right common carotid artery cytosine deaminase intimal hyperplasia vascular smooth muscle cells 5-fluorocytosine ionizing radiation intimal/medial Induction Hyperplasia Rabbit Cardiovascular disease Proliferation Lagomorpha Experimental study Radiotherapy Vascular disease Restenosis Vertebrata Mammalia Treatment Animal Blood vessel Intima Biological effect Inhibition Gene therapy
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Summary:	Background. Although ionizing radiation (IR) has been demonstrated to attenuate vessel wall restenosis and intimal hyperplasia (IH), dose-related mural injury and atrophy are possible deleterious side effects. We tested the hypothesis that a radiosensitizing strategy may improve IR-induced inhibition of in vivo vascular smooth muscle cells (VSMCs) without influencing apoptotic cell death. Methods. In 28 New Zealand White rabbits, the right common carotid artery (CCA) was injured and subjected to low-flow conditions to promote IH. The CCA was transfected with an adenoviral vector incorporating the cytosine deaminase (CD) gene (1 × 109 PFU/ml). 5-Fluorocytosine (5-FC), a prodrug that is converted to the radiosensitizing agent 5-fluorouracil (5-FU) by CD, was thereafter administered intravenously. The CCA was exposed to 5 Gy IR at 24 h. Intimal/medial (I/M) area and thickness ratios were determined in the harvested CCAs at 14 days. VSMC proliferative and apoptotic indices were assessed with immunohistochemistry. Results. A 50% reduction in I/M area was found in rabbits treated with IR and IR + CD/5-FC (0.19 ± 0.03 and 0.18 ± 0.02) when compared with untreated controls (UC) (0.37 ± 0.06) (P = 0.005). This finding was substantiated by attenuation of I/M thickness in the IR groups [0.47 ± 0.13 (IR), 0.41 ± 0.11 (IR + CD/5-FC), 0.61 ± 0.17 (UC)] (P = 0.007). The number of proliferating VSMCs was notably smaller when IR was combined with CD/5-FC (4.17 ± 1.16 vs 2.97 ± 1.09 log transformed cells/mm2, P < 0.07). Apoptosis was similar in all groups. Conclusions. Both IR alone and IR combined with a radiosensitizing agent are effective in attenuating experimental IH. However, combination therapy is synergistic and achieves greater inhibition of VSMC proliferation and may involve selective killing of radioresistant S-phase VSMCs. IR + CD/5-FC represents a novel therapeutic strategy that offers potential for long-term control of IH.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-4804 1095-8673
DOI:	10.1006/jsre.2000.5814