Prevention of smooth muscle cell outgrowth from human atherosclerotic plaque by a recombinant cytotoxin specific for the epidermal growth factor receptor

• Published in: The Journal of clinical investigation Vol. 91; no. 2; pp. 724 - 729
• Main Authors: PICKERING, J. G, BACHA, P. A, WEIR, L, JAKANOWSKI, J, NICHILS, J. C, ISNER, J. M
• Format: Journal Article
• Language: English
• Published: Ann Arbor, MI American Society for Clinical Investigation 01-02-1993
• Subjects: Arteriosclerosis - pathology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Division - drug effects; Cells, Cultured; Diphtheria Toxin - pharmacology; Epidermal Growth Factor - pharmacology; Humans; Medical sciences; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - pathology; Receptor, Epidermal Growth Factor - drug effects; Receptor, Epidermal Growth Factor - physiology; Recombinant Fusion Proteins - pharmacology; Human; Cell culture; Membrane receptor; Epidermal growth factor; Treatment; Immunotherapy; Blood vessel; Atherosclerosis; Cardiovascular disease; Smooth muscle
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI116254

Smooth muscle cell proliferation in the intima of arteries is a principal event associated with vascular narrowing after balloon angioplasty and bypass surgery. Techniques for limiting smooth muscle cell proliferation, however, have not as yet yielded any therapeutic benefit for these conditions. This may reflect the present lack of sufficiently potent and specific inhibitors of smooth muscle cell proliferation. DAB389 EGF is a genetically engineered fusion protein in which the receptor-binding domain of diphtheria toxin has been replaced by human epidermal growth factor. We evaluated the effect of this fusion toxin on human vascular smooth muscle cells in culture. Incubation of proliferating cells with DAB389 EGF yielded a dose-dependent inhibition of protein synthesis, as assessed by uptake of [3H]leucine, with an IC50 of 40 pM. The cytotoxic effect was inhibited in the presence of excess EGF or with monoclonal antibody to the EGF receptor. We further studied the effect of the fusion toxin on smooth muscle cell outgrowth from human atherosclerotic plaque. Outgrowth was markedly inhibited after as little as 1 h of exposure to the fusion protein. Furthermore, complete inhibition of proliferation of cells within the plaque could be attained. These results demonstrate that DAB389 EGF is highly cytotoxic to human smooth muscle cells proliferating in culture and can prevent smooth muscle cell outgrowth from "growth-stimulated" human atherosclerotic plaque. DAB389 EGF may therefore be of therapeutic value in vascular diseases characterized by smooth muscle cell accumulation.