Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion

Abstract

Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-a) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-a in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-a 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-a. IHP with melphalan alone resulted, in all tumour types, in a decreased growth rate. However in the BN-175 tumour addition of TNF-a 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-a, ruling out a direct interaction of TNF-a with tumour cells. The response rate in BN-175 tumour-bearing rats when TNF-a 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-a mediated effects. Assessment of the tumour vasculature of liver metastases would be a way of establishing an indication for the utility of TNF-a in this setting.

Tumor necrosis factor, cancer and anticancer therapy

“…Although low-dose TNF has a favorable effect on angiogenesis, higher doses cause destruction of newly formed blood vessels [38]. Concordantly, TNF induces a dose-dependent reduction of tumor blood flow [39,40], and the degree of tumor vascularization directly correlates with tumor response to TNF-based treatment both in animal and human models [34,[41][42][43].…”

Dynamic contrast-enhanced MRI using macromolecular contrast media for monitoring the response to isolated limb perfusion in experimental soft-tissue sarcomas

“…TNF-α is directly cytotoxic for tumor cells [2] and has indirect toxicity by affecting endothelial cells and tumor vascularization [3][4][5]. By combining TNF-α and a cytostatic drug like melphalan, a synergistic effect on the tumor activity can be obtained, because of an immediate TNF-mediated tumorselective enhanced drug uptake of the cytostatic agent [6,7], dependent on the vascularity of the tumor [8], followed by a tumor-selective eradication of the tumor-associated vasculature [9]. In the clinical setting the combination of TNF-α, interferon-γ and melphalan in isolated limb perfusion has lead to a limb salvage rate of 90% in isolated limb perfusion for irresectable melanomas and sarcomas [9][10][11].…”

Immune and Anti-oxidant Functions of Ethanol Extracts of Scutellaria baicalensis Georgi in Mice Bearing U14 Cervical Cancers

“…In some studies IL-2 has been shown to have powerful anti-tumor effects and has been used for the treatment of melanoma and renal cell carcinoma in the clinic (Overwijk et al, 2000). TNF-α is a multifunctional cytokine that possesses anti-tumor activity including destruction of the tumor endothelial cells, increasing vascular permeability (van Etten et al, 2003), inhibition of tumor angiogenesis mediated by generation of angiostatin (Mauceri et al, 2002). TNF-α can not only inhibit the growth of tumor cells but also kill tumor cells directly through cytolysis.…”