Local infusion of FGF-saporin reduces intimal hyperplasia.
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.
Mattar
S G
SG
Division of Vascular Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30033, USA.
Hanson
S R
SR
Pierce
G F
GF
Chen
C
C
Hughes
J D
JD
Cook
J E
JE
Shen
C
C
Noe
B A
BA
Suwyn
C R
CR
Scott
J R
JR
Lumsden
A B
AB
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D002455:Cell Division / Q000187:drug effects; D004285:Dogs; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D006965:Hyperplasia; D000922:Immunotoxins; D008297:Male; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins
D000922:Immunotoxins; D010940:Plant Proteins; D011994:Recombinant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D004815:Epidermal Growth Factor; D009699:N-Glycosyl Hydrolases; D000076985:Saporins