Histamine’s vasoactive properties improving response rates in solid tumor treatment

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.

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