title: Synergistic antitumor response of interleukin 2 with melphalan in isolated limb perfusion in soft tissue sarcoma-bearing rats.
abstract: The cytokine interleukin 2 (IL-2) is a mediator of immune cell activation with some antitumor activity, mainly in renal cell cancer and melanoma. We have previously shown that tumor necrosis factor (TNF)-alpha has strong synergistic antitumor activity in combination with chemotherapeutics in the isolated limb perfusion (ILP) setting based on a TNF-mediated enhanced tumor-selective uptake of the chemotherapeutic drug followed by a selective destruction of the tumor vasculature. IL-2 can cause vascular leakage and edema and for this reason we examined the antitumor activity of a combined treatment with IL-2 and melphalan in our well-established ILP in soft tissue sarcoma-bearing rats (BN175). ILP with either IL-2 or melphalan alone has no antitumor effect, but the combination of IL-2 and melphalan resulted in a strong synergistic tumor response, without any local or systemic toxicity. IL-2 enhanced significantly melphalan uptake in tumor tissue. No signs of significant vascular damage were detected to account for this observation, although the tumor sections of the IL-2- and IL-2 plus melphalan-treated animals revealed scattered extravasation of erythrocytes compared with the untreated animals. Clear differences were seen in the localization of ED-1 cells, with an even distribution in the sham, IL-2 and melphalan treatments, whereas in the IL-2 plus melphalan-treated tumors clustered ED-1 cells were found. Additionally, increased levels of TNF mRNA were found in tumors treated with IL-2 and IL-2 plus melphalan. These observations indicate a potentially important role for macrophages in the IL-2-based perfusion. The results in our study indicate that the novel combination of IL-2 and melphalan in ILP has synergistic antitumor activity and may be an alternative for ILP with TNF and melphalan.
authors.affiliation: Department of Surgical Oncology, Erasmus MC, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands.
authors.forename: Saske
authors.initials: S
authors.lastname: Hoving
authors.forename: Flavia
authors.initials: F
authors.lastname: Brunstein
authors.forename: Gisela
authors.initials: G
authors.lastname: aan de Wiel-Ambagtsheer
authors.forename: Sandra T
authors.initials: ST
authors.lastname: van Tiel
authors.forename: Gert
authors.initials: G
authors.lastname: de Boeck
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*; D017209:Apoptosis / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006614:Hindlimb; D006863:Hydrogen-Ion Concentration; D007376:Interleukin-2 / Q000008:administration & dosage; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D011914:Rats, Inbred BN; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D007376:Interleukin-2; D008558:Melphalan