Mattar S G, Hanson S R, Pierce G F, Chen C, Hughes J D, Cook J E, Shen C, Noe B A, Suwyn C R, Scott J R, Lumsden A B
Division of Vascular Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30033, USA.
J Surg Res. 1996 Feb 1;60(2):339-44. doi: 10.1006/jsre.1996.0054.
The recent conjugation of the potent ribosome-inactivating protein saporin (SAP) with basic fibroblast growth factor (FGF2) to form recombinant (r)FGF2-SAP permits increased selectivity of this mitoxin for cells exhibiting upregulated FGF receptors. Systemic administration of rFGF-SAP in therapeutic doses, however, may be associated with significant liver toxicity. In this blinded study, we used a local boundary layer infusion approach to increase local drug concentration while minimizing the risk of side effects. Six dogs underwent bilateral carotid endarterectomies. Expanded polytetrafluoroethylene infusion devices, blindly primed with rFGF2-SAP to one artery or vehicle to the contralateral vessel, were anastomosed proximal to the injured segments so that each animal served as its own control. rFGF2-SAP (2 microgram/kg/day) or vehicle (5 microl/hr) was continuously delivered for 14 days from an osmotic reservoir, through the wall of the graft infusion device. Euthanasia was carried out at 14 days and the processed arteries were blindly analyzed for intimal thickening and cellular proliferation. All dogs survived until sacrifice with no clinical side effects. Liver function tests at euthanasia were not significantly altered when compared to baseline values. Intimal area in rFGF2-SAP-treated vessels averaged 0.31 +/- 0.10 mm2 versus 0.57 +/- 0.24 mm2 in the control segments (P = 0.02), a relative reduction of 46%. Cell proliferation, however, was not significantly different at 14 days postendarterectomy (2.40 +/- 1.31% vs 2.39 +/- 0.45%). From this study it can be concluded that locally delivered rFGF2-SAP reduces intimal hyperplasia and that the boundary layer infusion strategy is an effective means for delivering high local drug concentration while minimizing systemic drug effects.
最近，强效核糖体失活蛋白皂草素（SAP）与碱性成纤维细胞生长因子（FGF2）偶联形成重组（r）FGF2 - SAP，使得这种促细胞分裂毒素对FGF受体上调的细胞具有更高的选择性。然而，以治疗剂量全身给药rFGF - SAP可能会伴有显著的肝脏毒性。在这项双盲研究中，我们采用局部边界层输注方法来提高局部药物浓度，同时将副作用风险降至最低。六只狗接受了双侧颈动脉内膜切除术。将用rFGF2 - SAP或赋形剂盲目灌注的膨体聚四氟乙烯输注装置分别吻合到一侧动脉和对侧血管的损伤段近端，这样每只动物都作为自身对照。通过渗透储液器，从移植输注装置壁持续14天给予rFGF2 - SAP（2微克/千克/天）或赋形剂（5微升/小时）。在第14天实施安乐死，并对处理后的动脉进行盲法分析，以检测内膜增厚和细胞增殖情况。所有狗均存活至处死，无临床副作用。与基线值相比，安乐死时的肝功能测试无显著变化。rFGF2 - SAP处理血管的内膜面积平均为0.31±0.10平方毫米，而对照段为0.57±0.24平方毫米（P = 0.02），相对减少了46%。然而，动脉内膜切除术后14天时细胞增殖无显著差异（2.40±1.31%对2.39±0.45%）。从这项研究可以得出结论，局部递送rFGF2 - SAP可减少内膜增生，并且边界层输注策略是一种在将全身药物效应降至最低的同时递送高局部药物浓度的有效方法。
