EFFECTS OF A RECOMBINANT TOXIN TARGETED TO THE SMOOTH MUSCLE CELLS FF RECEPTOR

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The dominant mechanism responsible for restenosis after angioplasty is believed to be the activation of medial smooth muscle cells (SMC), leading to their proliferation, migration to the subintima, and further proliferation. To develop novel strategies that might inhibit or prevent restenosis, we previously used a chimeric toxin composed of TGFalpha (which targets the EGF receptor) and mutated Pseudomonas exotoxin to preferentially recognize and kill rapidly proliferating, vs quiescent, vascular SMC. We have recently cloned and expressed a recombinant gene encoding Pseudomonas exotoxin with a mutated (nonfunctional) cell recognition domain fused with the ligand acidic FGF; thus, this recombinant toxin targets the FGF receptor. In the present study we evaluated the relative effects of this chimeric toxin on quiescent vs. rapidly proliferating vascular SMC, and also determined whether it exerted different effects on SMC vs. endothelial cells. Rapidly proliferating SMCs were very sensitive to its cytotoxic effects, whereas cytotoxicity was significantly less when the SMCs were in a quiescent state. The chimeric toxin was also significantly less cytotoxic against endothelial cells. Thus, these studies suggest a potentially expanded role of recombinant toxin therapy in restenosis: multiple receptors can be targeted, and cytotoxic effects, at least in vitro, can be preferentially directed to rapidly proliferating vascular SMC, with relative sparing of vascular endothelial cells.