title: Synergistic antitumour effect of TNF-SAM2 with melphalan and doxorubicin in isolated limb perfusion in rats.
abstract: An isolated limb perfusion model (ILP) using soft tissue sarcoma bearing rats (BN175) was used to study antitumour activity of a tumour necrosis factor alpha mutant (TNF-SAM2) in combination with melphalan and doxorubicin. Progressive disease was demonstrated after ILP without agents (sham) or with 50 micrograms TNF-SAM2. ILP with 40 micrograms melphalan or 400 micrograms doxorubicin resulted in no change of tumour volume or progressive disease five days after perfusion. Partial and complete response rates were demonstrated in 76% of rats when the combination of TNF-SAM2 and melphalan was used. TNF-SAM2 in combination with doxorubicin was synergistic as well with a 70% response rate. Histopathologically these responses consisted of hemorrhagic necrosis of the coagulative type. 2 In conclusion, TNF-SAM2 has similar antitumour activity in combination with melphalan or doxorubicin as rHuTNF in sarcoma-bearing rats and is eligible to be tested in clinical ILP or organ perfusion settings because of its potential decreased toxicity.
authors.affiliation: Department of Surgical Oncology, University Hospital Rotterdam-Dr Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: de Wilt
authors.forename: G
authors.initials: G
authors.lastname: Soma
authors.forename: T L
authors.initials: TL
authors.lastname: ten Hagen
authors.forename: J
authors.initials: J
authors.lastname: Kanou
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: P T
authors.initials: PT
authors.lastname: Nooijen
authors.forename: A L
authors.initials: AL
authors.lastname: Seynhaevel
authors.forename: A M
authors.initials: AM
authors.lastname: Eggermont
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D010478:Chemotherapy, Cancer, Regional Perfusion; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity; D006614:Hindlimb; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000633:toxicity; D009368:Neoplasm Transplantation; D051381:Rats; D011914:Rats, Inbred BN; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000633:toxicity
chemical_list: C109083:TNF-SAM2; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D008558:Melphalan