BACKGROUND: The plant cytotoxin saporin (SAP) is a potent ribosome-inactivating protein. When conjugated to basic fibroblast growth factor (FGF2), it selectively kills proliferating cells that have upregulated FGF receptors. In this study, we evaluated the effect of the recombinant chimeric mitotoxin rFGF2-SAP on venous anastomotic intimal hyperplasia, a major cause of failure of arteriovenous (AV) grafts. METHODS AND RESULTS: Recently designed expanded polytet-rafluoroethylene-based local infusion devices were implanted bilaterally as femoral AV conduits in six dogs. The venous anastomoses were the sites of continuous delivery of rFGF2-SAP (2.7 micrograms.kg-1.d-1) to one side and vehicle (4.6 microL.kg-1.d-1) as control to the contralateral side for 14 days. All animals survived, and all grafts were patent. Liver enzyme levels and histological analyses of liver, kidneys, and brain were normal, indicating the absence of systemic toxicity. Morphometric measurements and measurements of cell proliferation by bromodeoxyuridine index analysis were performed at both arterial and venous anastomoses. There were no significant differences between the treated grafts and the control grafts in intimal hyperplasia and intimal cell proliferation at the arterial anastomoses. In contrast, rFGF2-SAP reduced intimal thickness by 32%, intimal area by 40%, and cell proliferation index by 33% at the treated venous anastomoses compared with the control venous anastomoses (P < .05). CONCLUSIONS: These data demonstrate that local infusion of rFGF2-SAP significantly reduces venous anastomotic intimal hyperplasia and cell proliferation without systemic toxicity. This study suggests a new strategy for reducing intimal hyperplasia by the selective killing of proliferating smooth muscle cells with a potent chimeric mitotoxin through a novel local infusion device.
BACKGROUND: The plant cytotoxin saporin (SAP) is a potent ribosome-inactivating protein. When conjugated to basic fibroblast growth factor (FGF2), it selectively kills proliferating cells that have upregulated FGF receptors. In this study, we evaluated the effect of the recombinant chimeric mitotoxin rFGF2-SAP on venous anastomotic intimal hyperplasia, a major cause of failure of arteriovenous (AV) grafts. METHODS AND RESULTS: Recently designed expanded polytet-rafluoroethylene-based local infusion devices were implanted bilaterally as femoral AV conduits in six dogs. The venous anastomoses were the sites of continuous delivery of rFGF2-SAP (2.7 micrograms.kg-1.d-1) to one side and vehicle (4.6 microL.kg-1.d-1) as control to the contralateral side for 14 days. All animals survived, and all grafts were patent. Liver enzyme levels and histological analyses of liver, kidneys, and brain were normal, indicating the absence of systemic toxicity. Morphometric measurements and measurements of cell proliferation by bromodeoxyuridine index analysis were performed at both arterial and venous anastomoses. There were no significant differences between the treated grafts and the control grafts in intimal hyperplasia and intimal cell proliferation at the arterial anastomoses. In contrast, rFGF2-SAP reduced intimal thickness by 32%, intimal area by 40%, and cell proliferation index by 33% at the treated venous anastomoses compared with the control venous anastomoses (P < .05). CONCLUSIONS: These data demonstrate that local infusion of rFGF2-SAP significantly reduces venous anastomotic intimal hyperplasia and cell proliferation without systemic toxicity. This study suggests a new strategy for reducing intimal hyperplasia by the selective killing of proliferating smooth muscle cells with a potent chimeric mitotoxin through a novel local infusion device.