Synergistic Antitumor Activity of Histamine Plus Melphalan in Isolated Limb Perfusion: Preclinical Studies
2004
textabstractBACKGROUND: 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. METHODS: 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.
RESULTS: 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. CONCLUSIONS: 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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