title: Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-alpha-based isolated hepatic perfusion.
abstract: Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-alpha) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-alpha in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-alpha 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-alpha. IHP with melphalan alone resulted, in all tumour types, in a decreased growth rate. However in the BN-175 tumour addition of TNF-alpha 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-alpha, ruling out a direct interaction of TNF-alpha with tumour cells. The response rate in BN-175 tumour-bearing rats when TNF-alpha 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-alpha mediated effects. Assessment of the tumour vasculature of liver metastases would be a way of establishing an indication for the utility of TNF-alpha in this setting.
authors.affiliation: Department of Surgical Oncology, University Hospital Rotterdam-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: van Etten
authors.forename: M R
authors.initials: MR
authors.lastname: de Vries
authors.forename: M G A
authors.initials: MG
authors.lastname: van IJken
authors.forename: T E
authors.initials: TE
authors.lastname: Lans
authors.forename: G
authors.initials: G
authors.lastname: Guetens
authors.forename: G
authors.initials: G
authors.lastname: Ambagtsheer
authors.forename: S T
authors.initials: ST
authors.lastname: van Tiel
authors.forename: G
authors.initials: G
authors.lastname: de Boeck
authors.forename: E A
authors.initials: EA
authors.lastname: de Bruijn
authors.forename: A M M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: T L M
authors.initials: TL
authors.lastname: ten Hagen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D002455:Cell Division / Q000187:drug effects; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism; D004195:Disease Models, Animal; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D008114:Liver Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism* / Q000556:secondary; D008297:Male; D008558:Melphalan / Q000493:pharmacokinetics*; D008833:Microcirculation; D012516:Osteosarcoma / Q000098:blood supply / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D012509:Sarcoma / Q000098:blood supply / Q000378:metabolism; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan