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(Circulation Research. 1995;77:1-9.)
© 1995 American Heart Association, Inc.

Articles

Epidermal Growth Factor Receptor–Targeted Cytotoxin Inhibits Neointimal Hyperplasia In Vivo

Results of Local Versus Systemic Administration

Christopher J. Pastore, Jeffrey M. Isner, Patricia A. Bacha, Marianne Kearney, J. Geoffrey Pickering

From the Departments of Medicine (Cardiology), Pathology, and Biomedical Research (C.J.P., J.M.I., M.K., J.G.P.), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass; Seragen Inc (P.A.B.), Hopkinton, Mass; and the John P. Robarts Research Institute and Department of Medicine (Cardiology) (J.G.P.), University Hospital, University of Western Ontario, London, Canada.

Correspondence to Jeffrey M. Isner, St. Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135.

Abstract Smooth muscle cell accumulation is a key feature of restenosis that may be inhibited by the delivery of receptor-targeted cytotoxins. DAB₃₈₉EGF is a recombinant fusion protein in which the receptor-binding domain of diphtheria toxin has been replaced by human epidermal growth factor (EGF). We investigated the effectiveness of DAB₃₈₉EGF to inhibit neointimal hyperplasia in the balloon-injured rat carotid artery. Incubation of rat carotid arteries with ¹²⁵I-labeled EGF revealed extensive EGF binding sites in the neointima of balloon-injured arteries. Sixty rats subsequently received either saline or DAB₃₈₉EGF (total dose, 0.15 mg) delivered immediately following balloon injury either systemically, via 14-day continuous osmotic pump infusion, or locally, via 30-minute intraluminal incubation. The effect of both treatment strategies was measured 2 weeks after injury by cross-sectional morphometric analysis of intimal area, the ratio of intimal/medial area (I/M), and the percent luminal narrowing (%LN). In addition, proliferative activity was assessed by immunostaining for the presence of the proliferating cell nuclear antigen (PCNA). Compared with controls, systemic delivery of fusion toxin significantly reduced intimal area, I/M, and %LN by 40%, 40%, and 29%, respectively. However, these rats exhibited 2% weight loss, indicating mild systemic toxicity. Local, intraluminal administration of DAB₃₈₉EGF yielded a more pronounced reduction in intimal area, I/M, and %LN by 74%, 79%, and 72%, respectively. This inhibitory effect was preserved at 3 weeks postinjury, and PCNA immunostaining of locally treated arteries revealed a virtual absence of proliferative activity in the neointima and media at this timepoint. In contrast to systemically treated rats, rats receiving fusion toxin locally gained weight at a rate similar to controls, indicating avoidance of systemic toxicity. We conclude that DAB₃₈₉EGF is a potent inhibitor of neointimal hyperplasia in vivo and that whereas an inhibitory effect may be achieved by systemic delivery, local delivery appears to be more potent, avoids systemic toxicity, and thus represents a feasible strategy to preempt restenosis.

Key Words: vascular smooth muscle • epidermal growth factor • restenosis • fusion protein