Oral imatinib mesylate (STI571/gleevec) improves the efficacy of local intravascular vascular endothelial growth factor-C gene transfer in reducing neointimal growth in hypercholesterolemic rabbits.
BACKGROUND
Platelet-derived growth factor (PDGF) antagonists have demonstrated beneficial effects on neointima formation, but in studies using PDGF inhibitors and extended follow-up, the lesions reoccur. These findings implicate a need to combine targeting of PDGF with other strategies. Stimulation of reendothelialization by treatment with endothelial cell mitogens of the vascular endothelial growth factor (VEGF) family counteracts restenosis, but there are also concerns regarding the durability of the effect with this approach.


RESULTS
To explore whether a combined use of PDGF antagonist and stimulation of reendothelialization confers better results than each therapy alone, we combined systemic administration of imatinib mesylate (STI571/Gleevec, 10 mg/kg(-1) per d(-1)), a tyrosine kinase inhibitor with activity against PDGF receptors, with local intravascular adenovirus-mediated VEGF-C gene transfer (1.15x10(10) pfu) in cholesterol-fed, balloon-injured rabbits. Throughout the course of the STI571 therapy, the circulating concentrations were able to suppress PDGF receptor phosphorylation. At 3 weeks, the treatment with STI571 led to a transient decrease in intralesion macrophages and to an increase in intimal smooth muscle cell apoptosis. VEGF-C application reduced neointima formation and accelerated reendothelialization. However, none of the therapies alone reduced intimal thickening at a 6-week time point, whereas the combined treatment led to a persistent reduction (55% versus control) in lesion size at this time point.


CONCLUSIONS
Our study provides one of the first successful examples of gene therapy combined with a pharmacological treatment to modulate 2 distinct ligand-receptor signaling systems and suggests combination of local VEGF-C gene therapy with systemic inhibition of PDGF signaling as a novel principle to prevent intimal hyperplasia after vascular manipulations.
Leppänen
Olli
O
Ludwig Institute for Cancer Research, Uppsala, Sweden.
Rutanen
Juha
J
Hiltunen
Mikko O
MO
Rissanen
Tuomas T
TT
Turunen
Mikko P
MP
Sjöblom
Tobias
T
Brüggen
Josef
J
Bäckström
Gudrun
G
Carlsson
Marianne
M
Buchdunger
Elisabeth
E
Bergqvist
David
D
Alitalo
Kari
K
Heldin
Carl-Henrik
CH
Ostman
Arne
A
Ylä-Herttuala
Seppo
S
D000256:Adenoviridae / Q000235:genetics; D000284:Administration, Oral; D000818:Animals; D001158:Arteries; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement; D003131:Combined Modality Therapy; D004730:Endothelium, Vascular / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D000068877:Imatinib Mesylate; D008264:Macrophages / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D011817:Rabbits; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics*
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D042582:Vascular Endothelial Growth Factor C; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor