The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model
- Hagen, Timo L.M. ten Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
- Seynhaeve, Ann L.B. Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
- Wiel-Ambagtsheer, Gisela aan de Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
- Bruijn, Ernst A. de Department of Experimental Oncology, University of Leuven, Leuven, Belgium
- Tiel, Sandra T. van Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
- Rüegg, Curzio Division of Experimental Oncology, Centre Pluridisciplinaire d'Oncologie, University of Lausanne, Switzerland - Pathology, Department of Medicine, Faculty of Sciences, University of Fribourg and Swiss Institute for Experimental Cancer Research, NCCR Molecular Oncology, Epalinges, Switzerland
- Meyring, Michael Merck KGaA, Institute of Drug Metabolism and Pharmacokinetics, Grafing, Germany
- Grell, Matthias Merck KGaA, Oncology Research and Development, Darmstadt, Germany
- Goodman, Simon L. Merck KGaA, Oncology Research and Development, Darmstadt, Germany
- Eggermont, Alexander M.M. Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands - Institut de Cancérologie Gustave Roussy, Villejuif/Paris, France
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05.12.2012
Published in:
- International Journal of Cancer. - 2013, vol. 132, no. 11, p. 2694-2704
English
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.
- Faculty
- Faculté des sciences et de médecine
- Department
- Médecine 3ème année
- Language
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- English
- Classification
- Biological sciences
- License
- License undefined
- Identifiers
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- RERO DOC 31055
- DOI 10.1002/ijc.27940
- Persistent URL
- https://folia.unifr.ch/unifr/documents/302640
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