title: Early destruction of tumor vasculature in tumor necrosis factor-alpha-based isolated limb perfusion is responsible for tumor response.
abstract: Addition of high-dose tumor necrosis factor-alpha to melphalan-based isolated limb perfusion enhances anti-tumor effects impressively. Unfortunately, the mechanism of action of tumor necrosis factor-alpha is still not fully understood. Here, we investigated the effects of tumor necrosis factor-alpha 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-alpha 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-alpha 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-alpha and no clear immune effects, cellular infiltration or cytokine expression were observed. Taken together, these results indicate that tumor necrosis factor-alpha 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.
authors.affiliation: Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, 3000 DR Rotterdam, The Netherlands.
authors.forename: Saske
authors.initials: S
authors.lastname: Hoving
authors.forename: Ann L B
authors.initials: AL
authors.lastname: Seynhaeve
authors.forename: Sandra T
authors.initials: ST
authors.lastname: van Tiel
authors.forename: Gisela
authors.initials: G
authors.lastname: aan de Wiel-Ambagtsheer
authors.forename: Ernst A
authors.initials: EA
authors.lastname: de Bruijn
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: Timo L M
authors.initials: TL
authors.lastname: ten Hagen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D002199:Capillary Permeability / Q000187:drug effects; D010478:Chemotherapy, Cancer, Regional Perfusion; D016207:Cytokines / Q000378:metabolism; D006614:Hindlimb / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D023421:Models, Animal; D051381:Rats; D011914:Rats, Inbred BN; D012513:Sarcoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan