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

A. H. Van Der Veen, J. H.W. De Wilt, A. M.M. Eggermont, S. T. Van Tiel, A. L.B. Seynhaeve, T. L.M. Ten Hagen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

135 Citations (Scopus)

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-α). This is in line with observations in patients. Here we show that ILP with doxorubicin in combination with TNF-α has comparable effects in two different rat sarcoma tumour models. The addition of TNF-α 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-α on the activity of cytotoxic agents in ILP is still unclear. We investigated possible modes by which TNF-α 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-α 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-α fails to augment drug uptake in tumour cells or to increase cytotoxicity of the drug. These findings make it unlikely that TNF-α directly modulates the activity of doxorubicin in vivo. As TNF-α 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. (C) 2000 Cancer Research Campaign.

Original languageEnglish
Pages (from-to)973-980
Number of pages8
JournalBritish Journal of Cancer
Volume82
Issue number4
DOIs
Publication statusPublished - 20 Jan 2000

Bibliographical note

© 2000 Cancer Research Campaign
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

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