2003-01-27
Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion
Publication
Publication
British Journal of Cancer , Volume 88 - Issue 2 p. 314- 319
Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-α) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-α in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-α contributes to the therapeutic efficacy in IHP still remains unclear. In an in vivo rat liver metastases model we studied three different tumours: colon carcinoma CC531, ROS-1 osteosarcoma and BN-175 soft-tissue sarcoma which exhibit different degrees of vascularisation. IHP was performed with melphalan with or without the addition of TNF-α. IHP with melphalan alone resulted, in all tumour types, in a decreased growth rate. However in the BN-175 tumour addition of TNF-α resulted in a strong synergistic effect. In the majority of the BN-175 tumour-bearing rats, a complete response was achieved. In vitro cytoxicity studies showed no sensitivity (CC531 and BN-175) or only minor sensitivity (ROS-1) to TNF-α, ruling out a direct interaction of TNF-α with tumour cells. The response rate in BN-175 tumour-bearing rats when TNF-α was coadministrated with melphalan was strongly correlated with drug accumulation in tumour tissue, as only in these rats a five-fold increased melphalan concentration was observed. Secondly, immunohistochemical analysis of microvascular density (MVD) of the tumour showed a significantly higher MVD for BN-175 tumour compared to CC531 and ROS-1. These results indicate a direct relation between vascularity of the tumour and TNF-α mediated effects. Assessment of the tumour vasculature of liver metastases would be a way of establishing an indication for the utility of TNF-α in this setting.
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| doi.org/10.1038/sj.bjc.6600707, hdl.handle.net/1765/69754 | |
| British Journal of Cancer | |
| Organisation | Department of Surgery |
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van Etten, B., de Vries, M., van IJken, M., Lans, T., Guetens, G., Aan de Wiel-Ambagtsheer, G., … ten Hagen, T. (2003). Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion. British Journal of Cancer, 88(2), 314–319. doi:10.1038/sj.bjc.6600707 |
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