Poly(ADP-ribose) polymerase inhibition combined with irradiation: A dual treatment concept to prevent neointimal hyperplasia after endarterectomy

Carsten J. Beller, Jens Kosse, Tamás Radovits, Domokos Gerö, Robert Krempien, Marie Luise Gross, Irina Berger, Siegfried Hagl, Csaba Szabó, Gábor Szabó

    Research output: Contribution to journalArticle

    5 Scopus citations

    Abstract

    Purpose: In a rat model of endarterectomy we investigated the potential role of the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway in neointima formation and the effects of irradiation, pharmacologic inhibition of PARP, or combined pharmacologic inhibition of PARP and irradiation on vascular remodeling. Methods and Materials: Carotid endarterectomy was performed by incision of the left carotid artery with removal of intima in Sprague-Dawley rats. Six groups were studied: sham-operated rats (n = 10), control endarterectomized rats (n = 10), or endarterectomized rats irradiated with 15 Gy (n = 10), or treated with PARP inhibitor, INO-1001 (5 mg/kg/day) (n = 10), or with combined treatment with INO-1001 and irradiation with 5 Gy (n = 10) or with 15 Gy (n = 10). After 21 days, neointima formation and vascular remodeling were assessed. Results: Neointima formation after endarterectomy was inhibited by postoperative irradiation with 15 Gy and was attenuated by PARP inhibition. However, in parallel to inhibition of neointimal hyperplasia, activation of the peroxynitrite-PARP pathway in the outer vessel wall layers was triggered by postoperative irradiation. Combined pharmacologic PARP inhibition and irradiation with 15 Gy significantly reduced both neointimal hyperplasia and activation of the peroxynitrite-PARP pathway in the outer vessel wall layers. Combination of PARP inhibition and irradiation with 5 Gy was less effective than both PARP inhibition or irradiation with 15 Gy alone. Conclusions: We conclude, that combined PARP inhibition and irradiation with 15 Gy may be a new dual strategy for prevention of restenosis after surgical vessel reconstruction: combining the strong antiproliferative effect of irradiation and ameliorating irradiation-induced side effects caused by excessive PARP activation.

    Original languageEnglish (US)
    Pages (from-to)867-875
    Number of pages9
    JournalInternational Journal of Radiation Oncology Biology Physics
    Volume66
    Issue number3
    DOIs
    StatePublished - Nov 1 2006

    Keywords

    • Endarterectomy
    • Irradiation
    • Neointima
    • Nitrosative stress
    • PARP inhibition

    ASJC Scopus subject areas

    • Radiation
    • Oncology
    • Radiology Nuclear Medicine and imaging
    • Cancer Research

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