The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

Authors

  • Timo L.M. ten Hagen,

    Corresponding author
    1. Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
    • Department of Surgery, Section Surgical Oncology, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
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    • Tel.: +31-10-4087682, Fax: +31-10-4089471

  • Ann L.B. Seynhaeve,

    1. Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
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  • Gisela aan de Wiel-Ambagtsheer,

    1. Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
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  • Ernst A. de Bruijn,

    1. Department of Experimental Oncology, University of Leuven, Leuven, Belgium
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  • Sandra T. van Tiel,

    1. Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
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  • Curzio Ruegg,

    1. Division of Experimental Oncology, Centre Pluridisciplinaire d'Oncologie, University of Lausanne and University Hospital, Lausanne, Switzerland
    2. Department of Medicine, Faculty of Sciences, University of Fribourg and Swiss Institute for Experimental Cancer Research, NCCR Molecular Oncology, Epalinges, Switzerland
    Current affiliation:
    1. Pathology, Department of Medicine, University of Fribourg, Fribourg, Switzerland
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  • Michael Meyring,

    1. Merck KGaA, Institute of Drug Metabolism and Pharmacokinetics, Grafing, Germany
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  • Matthias Grell,

    1. Merck KGaA, Oncology Research and Development, Darmstadt, Germany
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  • Simon L. Goodman,

    1. Merck KGaA, Oncology Research and Development, Darmstadt, Germany
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  • Alexander M.M. Eggermont

    1. Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
    2. Institut de Cancérologie Gustave Roussy, Villejuif/Paris, France
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  • Timo L.M. ten Hagen received an academic grant from Merck KGaA, Darmstadt, Germany. Ann L.B. Seynhaeve, Gisela aan de Wiel-Ambagtsheer, Sandra T. van Tiel, Curzio Ruegg, Ernst A. de Bruijn, and Alexander M.M. Eggermont have no relevant interests to disclose. Michael Meyring, Matthias Grell, and Simon L. Goodman are Merck KGaA employees

  • This article was published online on 5 December 2012. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected 20 December 2012.

Abstract

Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)-α is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better-tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha-V integrins, has both anti-angiogenic and direct anti-tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra-peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting.

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