TNF-alpha augments intratumoural concentrations of doxorubicin in TNF-alpha-based isolated limb perfusion in rat sarcoma models and enhances anti-tumour effects

We have shown previously that isolated limb perfusion (ILP) in sarcoma-bear ing rats results in high response rates when melphalan is used in combinati on with tumour necrosis factor alpha (TNF-alpha). This is in line with obse rvations 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 th e BN175-fibrosarcoma and the ROS-l osteosarcoma respectively. The combinati on 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 acti vity of doxorubicin. In both tumour models increased accumulation of doxoru bicin in tumour tissue was found: 3.1-fold in the BN175 and 1.8-fold in the ROS-l sarcoma after ILP with doxorubicin combined with TNF-alpha in compar ison with an ILP with doxorubicin alone. This increase in local drug concen tration may explain the synergistic anti-tumour responses after ILP with th e combination. In vitro TNF-alpha fails to augment drug uptake in tumour ce lls or to increase cytotoxicity of the drug. These findings make it unlikel y 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 inc rease in local concentrations of chemotherapeutic drugs might well be the m ain mechanism for the synergistic anti-tumour effects. (C) 2000 Cancer Rese arch Campaign.