Synergistic Antitumor Activity of Histamine Plus Melphalan in Isolated Limb Perfusion: Preclinical Studies

Department of Surgical Oncology, Erasmus MC, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Journal of the National Cancer Institute (Impact Factor: 12.58). 12/2004; 96(21):1603-10. DOI: 10.1093/jnci/djh300
Source: PubMed


We have previously shown how tumor response of isolated limb perfusion (ILP) with melphalan was improved when tumor necrosis factor alpha (TNF-alpha) was added. Taking into account that other vasoactive drugs could also improve tumor response to ILP, we evaluated histamine (Hi) as an alternative to TNF-alpha.
We used a rat ILP model to assess the combined effects of Hi and melphalan (n = 6) on tumor regression, melphalan uptake (n = 6), and tissue histology (n = 2) compared with Hi or melphalan alone. We also evaluated the growth of BN-175 tumor cells as well as apoptosis, necrosis, cell morphology, and paracellular permeability of human umbilical vein endothelial cells (HUVECs) after Hi treatment alone and in combination with melphalan.
The antitumor effect of the combination of Hi and melphalan in vivo was synergistic, and Hi-dependent reduction in tumor volume was blocked by H1 and H2 receptor inhibitors. Tumor regression was observed in 66% of the animals treated with Hi and melphalan, compared with 17% after treatment with Hi or melphalan alone. Tumor melphalan uptake increased and vascular integrity in the surrounding tissue was reduced after ILP treatment with Hi and melphalan compared with melphalan alone. In vitro results paralleled in vivo results. BN-175 tumor cells were more sensitive to the cytotoxicity of combined treatment than HUVECs, and Hi treatment increased the permeability of HUVECs.
Hi in combination with melphalan in ILP improved response to that of melphalan alone through direct and indirect mechanisms. These results warrant further evaluation in the clinical ILP setting and, importantly, in organ perfusion.

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Available from: Alexander Maximiliaan Eggermont
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    • "Specifically in the case of Hi, the batch used in this study was less active in vitro on both tumour and endothelial cells as compared to previous results (Brunstein et al, 2004), and possibly resulted in a partial loss of the direct effect of Hi towards tumour and endothelial cells in vivo. Strikingly, tumour endothelial lining destruction and haemorrhage remained similar after Hi-based ILP, quite comparable to previous results. "
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    ABSTRACT: Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents.
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    ABSTRACT: BACKGROUND: The treatment of locally advanced extremity soft tissue sarcoma poses a surgical challenge and may necessitate the amputation of the tumor-bearing extremity. Isolated limb perfusion with TNFα and melphalan was introduced as a neoadjuvant modality to facilitate limp-sparing surgery without influencing prognosis negatively. METHODS: Literature research of the PubMed database using Entrez, combined with the authors' experience. RESULTS: A limb salvage rate of approximately 80% and a local recurrence rate of 10–20% after delayed surgical resection have been reported and confirmed by multiple studies, with a low regional and systemic toxicity. CONCLUSIONS: TNFα-based isolated limb perfusion has revolutionized the treatment of locally advanced extremity soft tissue sarcomas. Further improvements are awaited after the introduction of new agents and novel approaches. GRUNDLAGEN: Lokal fortgeschrittene Weichgewebssarkome der Extremitäten stellen mit dem Ziel der lokalen Tumorkontrolle und dem gleichzeitigen Funktionserhalt eine stetige operative Herausforderung dar. Die isolierte hypertherme Extremitätenperfusion mit TNFα und Melphalan ist als neoadjuvante Therapieoption eingeführt worden, um Amputationen zu vermeiden, ohne die Prognose zu verschlechtern. METHODIK: Literaturrecherche über die PubMed Datenbank mittels Entrez, kombiniert mit den Erfahrungen der Autoren. ERGEBNISSE: Anhand mehrerer Studien wurde belegt, dass durch die ILP ein Extremitätenerhalt in bis zu 80 % der Fälle bei tolerablen lokalen und systemischen Komplikationen zu realisieren ist. Die Lokalrezidivrate liegt zwischen 10–20 %. SCHLUSSFOLGERUNGEN: Die isolierte Extremitätenperfusion mit TNFα und Melphalan hat die Behandlung von lokal fortgeschrittenen Weichgewebssarkomen der Extremitäten durch eine deutliche Reduktion der Amputationsraten revolutioniert. Weitere Fortschritte können nach Einführung neuer Substanzen erwartet werden.
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