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Early destruction of tumor vasculature in tumor necrosis factor-α-based isolated limb perfusion is responsible for tumor response

Hoving, Saskea; Seynhaeve, Ann L.B.a; van Tiel, Sandra T.a; aan de Wiel-Ambagtsheer, Giselaa; de Bruijn, Ernst A.b; Eggermont, Alexander M.M.a; ten Hagen, Timo L.M.a

doi: 10.1097/01.cad.0000224450.54447.b3

Addition of high-dose tumor necrosis factor-α to melphalan-based isolated limb perfusion enhances anti-tumor effects impressively. Unfortunately, the mechanism of action of tumor necrosis factor-α is still not fully understood. Here, we investigated the effects of tumor necrosis factor-α on the tumor microenvironment and on secondary immunological events during and shortly after isolated limb perfusion in soft-tissue sarcoma-bearing rats. Already during isolated limb perfusion, softening of the tumor was observed. Co-administration of tumor necrosis factor-α in the isolated limb perfusion with melphalan induced a six-fold enhanced drug accumulation of melphalan in the tumor compared with isolated limb perfusion with melphalan alone. In addition, directly after perfusion with tumor necrosis factor-α plus melphalan, over a time-frame of 30 min, vascular destruction, erythrocyte extravasation and hemorrhage was detected. Interstitial fluid pressure and pH in the tumor, however, were not altered by tumor necrosis factor-α and no clear immune effects, cellular infiltration or cytokine expression were observed. Taken together, these results indicate that tumor necrosis factor-α induces rapid damage to the tumor vascular endothelial lining resulting in augmented drug accumulation. As other important parameters were not changed (e.g. interstitial fluid pressure and pH), we speculate that the tumor vascular changes, and concurrent hemorrhage and drug accumulation are the key explanations for the observed synergistic anti-tumor response.

aDepartment of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

bDepartment of Experimental Oncology, University of Leuven, Leuven, Belgium

Correspondence to T.L.M. ten Hagen, Department of Surgical Oncology, Laboratory of Experimental Surgical Oncology, Erasmus MC, Room Ee 10104, PO Box 1738, 3000 DR Rotterdam, The Netherlands

Tel: +31 10 408 7682; fax: +31 10 408 9471;


Sponsorship: This study was supported by grant DDHK 2000-2224 of the Dutch Cancer Society and a grant of the Foundation ‘Stichting Erasmus Heelkundig Kankeronderzoek’ and Boehringer Ingelheim GmbH by means of generous supply of tumor necrosis factor-α.

Received 5 April 2006 Accepted 15 May 2006

© 2006 Lippincott Williams & Wilkins, Inc.