Published Online
on February 9, 2004

A more recent version of this article appeared on March 9, 2004

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Submitted on March 25, 2003
Revised on October 29, 2003
Accepted on October 29, 2003

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

Olli Leppänen MD, Juha Rutanen MD, Mikko O. Hiltunen MD, PhD, Tuomas T. Rissanen MD, PhD, Mikko P. Turunen PhD, Tobias Sjöblom PhD, Josef Brüggen PhD, Gudrun Bäckström BSc, Marianne Carlsson BSc, Elisabeth Buchdunger PhD, David Bergqvist MD, PhD, Kari Alitalo MD, PhD, Carl-Henrik Heldin PhD, Arne Östman PhD, and Seppo Ylä-Herttuala MD, PhD, FESC^*

From Ludwig Institute for Cancer Research (O.L., T.S., G.B., C.-H.H., A.Ö.), Uppsala, Sweden; A.I. Virtanen Institute (J.R., M.O.H., M.P.T., T.T.R., S.Y.-H.), University of Kuopio, and Gene Therapy Unit (J.R., M.O.H., M.P.T., T.T.R., S.Y.-H.), Kuopio University Hospital, Kuopio, Finland; Novartis Pharma AG (J.B., E.B.), Oncology Research, Novartis, Basel, Switzerland; Division of Vascular Surgery (O.L., M.C., D.B.), Uppsala University Hospital, Uppsala, Sweden; and Biomedicum (K.A.), University of Helsinki, Helsinki, Finland.

^* To whom correspondence should be addressed. E-mail: seppo.ylaherttuala{at}uku.fi.

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.

Methods and 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 (1.15x10¹⁰ 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.

Key words: restenosis • gene therapy • platelet-derived factors

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