title: TNF-alpha augments intratumoural concentrations of doxorubicin in TNF-alpha-based isolated limb perfusion in rat sarcoma models and enhances anti-tumour effects.
abstract: We have shown previously that isolated limb perfusion (ILP) in sarcoma-bearing rats results in high response rates when melphalan is used in combination with tumour necrosis factor alpha (TNF-alpha). This is in line with observations in patients. Here we show that ILP with doxorubicin in combination with TNF-alpha has comparable effects in two different rat sarcoma tumour models. The addition of TNF-alpha exhibits a synergistic anti-tumour effect, resulting in regression of the tumour in 54% and 100% of the cases for the BN175-fibrosarcoma and the ROS-1 osteosarcoma respectively. The combination is shown to be mandatory for optimal tumour response. The effect of high dose TNF-alpha on the activity of cytotoxic agents in ILP is still unclear. We investigated possible modes by which TNF-alpha could modulate the activity of doxorubicin. In both tumour models increased accumulation of doxorubicin in tumour tissue was found: 3.1-fold in the BN175 and 1.8-fold in the ROS-1 sarcoma after ILP with doxorubicin combined with TNF-alpha in comparison with an ILP with doxorubicin alone. This increase in local drug concentration may explain the synergistic anti-tumour responses after ILP with the combination. In vitro TNF-alpha fails to augment drug uptake in tumour cells or to increase cytotoxicity of the drug. These findings make it unlikely that TNF-alpha directly modulates the activity of doxorubicin in vivo. As TNF-alpha by itself has no or only minimal effect on tumour growth, an increase in local concentrations of chemotherapeutic drugs might well be the main mechanism for the synergistic anti-tumour effects.
authors.affiliation: Department of Surgical Oncology, University Hospital Rotterdam/Daniel den Hoed Cancer Center, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: van der Veen
authors.forename: J H
authors.initials: JH
authors.lastname: de Wilt
authors.forename: A M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: S T
authors.initials: ST
authors.lastname: van Tiel
authors.forename: A L
authors.initials: AL
authors.lastname: Seynhaeve
authors.forename: T L
authors.initials: TL
authors.lastname: ten Hagen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010478:Chemotherapy, Cancer, Regional Perfusion; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D051381:Rats; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin