Article

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.
CancerSpectrum Knowledge Environment (Impact Factor: 14.07). 12/2004; 96(21):1603-10. DOI: 10.1093/jnci/djh300
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
80 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The limb model of in-transit disease can expand our understanding of treating melanoma because of the ease of obtaining tissue biopsies for correlative studies and the availability of preclinical animal models that allow validation of novel therapeutic strategies. This review will focus on regional therapy for in-transit melanoma as a platform to investigate novel therapeutic approaches to improve regional disease control, and help us develop insights to more rationally design systemic therapy trials. J. Surg. Oncol. 2014 109:357-365. © 2013 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 03/2014; 109(4):357-65. DOI:10.1002/jso.23502 · 2.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Soft tissue sarcomas account for approximately 5000 new cases per year in Europe. 60% of them occur in the extremities and are often large at first diagnosis with a high propensity for hematogenic spread so that half of the patients die of disseminated disease. The use of aggressive approaches, such as amputation has no positive impact in survival rates, as compared to conservative approaches. In this sense, Isolated limb perfusion (ILP) plays a major role, consisting of the regional administration of high doses of drugs to an isolated limb. TNF/melphalan (TM-ILP) leads to overall response rates of circa 100% for melanoma patients and circa 70% for sarcoma patients, with a limb salvage index of approximately 75%. The mechanism of action of TNF is first a higher tumor drug uptake and secondarily the destruction of the tumor associated vasculature (TAV). Based on this success, there was a renewed interest in organ perfusion, unfortunately, the use of TNF in t! hese settings remains controversial with lack of confirmatory positive or synergistic responses in lung perfusion and with unacceptable hepatotoxicity in liver perfusion. In the Experimental Surgical Oncology experimental rat models of ILP and Isolated Hepatic Perfusion (IHP) were developed for a better understanding of the mechanism of action of these techniques and for the evaluation of new drugs. The aim of our study was to evaluate the potential use of Histamine, IL-2 and their combination, in the regional setting as an alternative to TNF. Hi showed a synergistic effect, when combined to doxorubicin in the experimental ILP, and when combined to melphalan in the experimental ILP and IHP. IL-2 also had a synergistic effect when combined to melphalan in the experimental ILP. Yet, the combination of Hi and IL-2 to melphalan in the ILP led to decreased response rates as compared to each agent alone combined to melphalan. The mechanism of action of Hi in the regional setting was very similar to the mechanism of action of TNF with a better tumor drug uptake, TAV destruction, and best responses seen with its combination to chemotherapeutic drugs.! Additionally, Hi had a direct cytotoxic effect against both tumor cells and TAV.
  • [Show abstract] [Hide abstract]
    ABSTRACT: When treating patients with solid tumors one is faced with a plethora of factors that may influence clinical outcome. Drugs tested with success on tumor cells in vitro do not always turn out to be that promising when used in humans. It is clear that although a drug may have strong activity on tumor cells in vitro, the usefulness of this drug also depends (for instance) on its availability when injected in the body. Factors such as pharmacokinetics, toxicity profile, intratumoral distribution, and activity in hypoxic or acidic regions are likely to be of even greater importance than the cytotoxic potential of a drug. To allow better prediction of the activity of a drug in the clinical setting, the use of clinically relevant animal models is imperative. Here we describe the use of animal models for solid tumor therapy and in particular regional treatment application.

Full-text (2 Sources)

Download
33 Downloads
Available from
May 20, 2014