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

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 t...

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Autores principales: van Etten, B, de Vries, M R, van IJken, M G A, Lans, T E, Guetens, G, Ambagtsheer, G, van Tiel, S T, de Boeck, G, de Bruijn, E A, Eggermont, A M M, ten Hagen, T L M
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2377047/
https://www.ncbi.nlm.nih.gov/pubmed/12610519
http://dx.doi.org/10.1038/sj.bjc.6600707
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author van Etten, B
de Vries, M R
van IJken, M G A
Lans, T E
Guetens, G
Ambagtsheer, G
van Tiel, S T
de Boeck, G
de Bruijn, E A
Eggermont, A M M
ten Hagen, T L M
author_facet van Etten, B
de Vries, M R
van IJken, M G A
Lans, T E
Guetens, G
Ambagtsheer, G
van Tiel, S T
de Boeck, G
de Bruijn, E A
Eggermont, A M M
ten Hagen, T L M
author_sort van Etten, B
collection PubMed
description 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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spelling pubmed-23770472009-09-10 Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion van Etten, B de Vries, M R van IJken, M G A Lans, T E Guetens, G Ambagtsheer, G van Tiel, S T de Boeck, G de Bruijn, E A Eggermont, A M M ten Hagen, T L M Br J Cancer Genetics and Genomics 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. Nature Publishing Group 2003-01-27 2003-01-28 /pmc/articles/PMC2377047/ /pubmed/12610519 http://dx.doi.org/10.1038/sj.bjc.6600707 Text en Copyright © 2003 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Genetics and Genomics
van Etten, B
de Vries, M R
van IJken, M G A
Lans, T E
Guetens, G
Ambagtsheer, G
van Tiel, S T
de Boeck, G
de Bruijn, E A
Eggermont, A M M
ten Hagen, T L M
Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion
title Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion
title_full Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion
title_fullStr Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion
title_full_unstemmed Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion
title_short Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-α-based isolated hepatic perfusion
title_sort degree of tumour vascularity correlates with drug accumulation and tumour response upon tnf-α-based isolated hepatic perfusion
topic Genetics and Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2377047/
https://www.ncbi.nlm.nih.gov/pubmed/12610519
http://dx.doi.org/10.1038/sj.bjc.6600707
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