title: Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion.
abstract: Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting.
authors.affiliation: Department of Surgical Oncology, Erasmus MC, Laboratory of Experimental Surgical Oncology, Daniel den Hoed Cancer Centre, Room Ee 0175, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands. flis_br@yahoo.com
authors.forename: Flavia
authors.initials: F
authors.lastname: Brunstein
authors.forename: Saske
authors.initials: S
authors.lastname: Hoving
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: Gunther
authors.initials: G
authors.lastname: Guetens
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; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002199:Capillary Permeability / Q000187:drug effects; D010478:Chemotherapy, Cancer, Regional Perfusion; D004357:Drug Synergism; D006632:Histamine / Q000008:administration & dosage; D018494:Histamine Agents / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000008:administration & dosage; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D051381:Rats; D011914:Rats, Inbred BN; D011994:Recombinant Proteins / Q000008:administration & dosage; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018494:Histamine Agents; D007376:Interleukin-2; D011994:Recombinant Proteins; D006632:Histamine; D008558:Melphalan