Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting.

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Keywords Histamine, IL-2, Regional treatment, Sarcomas
Persistent URL dx.doi.org/10.1007/s00262-006-0206-y, hdl.handle.net/1765/36108
Citation
Brunstein, F, Hoving, S, Aan de Wiel-Ambagtsheer, G, de Bruijn, E.A, Guetens, G, Eggermont, A.M.M, & ten Hagen, T.L.M. (2007). Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion. Cancer Immunology, Immunotherapy: other biological response modifications, 56(4), 573–580. doi:10.1007/s00262-006-0206-y