EPIDERMAL GROWTH-FACTOR RECEPTOR-TARGETED CYTOTOXIN INHIBITS NEOINTIMAL HYPERPLASIA IN-VIVO - RESULTS OF LOCAL VERSUS SYSTEMIC ADMINISTRATION

Smooth muscle cell accumulation is a key feature of restenosis that ma y be inhibited by the delivery of receptor-targeted cytotoxins. DAB(38 9)EGF is a recombinant fusion protein in which the receptor-binding do main of diphtheria toxin has been replaced by human epidermal growth f actor (EGF). We investigated the effectiveness of DAB(389)EGF to inhib it neointimal hyperplasia in the balloon-injured rat carotid artery. I ncubation of rat carotid arteries with I-125-labeled EGF revealed exte nsive EGF binding sites in the neointima of balloon-injured arteries. Sixty rats subsequently received either saline or DAB(389)EGF (total d ose, 0.15 mg) delivered immediately following balloon injury either sy stemically, via 14-day continuous osmotic pump infusion, or locally, v ia 30-minute intraluminal incubation. The effect of both treatment str ategies was measured 2 weeks after injury by cross-sectional morphomet ric analysis of intimal area, the ratio of intimal/medial area (I/M), and the percent luminal narrowing (%LN). In addition, proliferative ac tivity was assessed by immunostaining for the presence of the prolifer ating cell nuclear antigen (PCNA). Compared with controls, systemic de livery of fusion toxin significantly reduced intimal area, I/M, and %L N by 40%, 40%, and 29%, respectively. However, these rats exhibited 2% weight loss, indicating mild systemic toxicity. Local, intraluminal a dministration of DAB(389)EGF yielded a more pronounced reduction in in timal area, I/M, and %LN by 74%, 79%, and 72%, respectively. This inhi bitory effect was preserved at 3 weeks postinjury, and PCNA immunostai ning of locally treated arteries revealed a virtual absence of prolife rative activity in the neointima and media at this timepoint. In contr ast to systemically treated rats, rats receiving fusion toxin locally gained weight at a rate similar to controls, indicating avoidance of s ystemic toxicity. We conclude that DAB(389)EGF is a potent inhibitor o f neointimal hyperplasia in vivo and that whereas an inhibitory effect may be achieved by systemic delivery, local delivery appears to be mo re potent, avoids systemic toxicity, and thus represents a feasible st rategy to preempt restenosis.