In mast cell (MC) neoplasms, clinical problems requiring therapy include local aggressive
and sometimes devastating growth of MCs and mediator-related symptoms. A key mediator
of MCs responsible for clinical symptoms is histamine. Therefore, use of histamine
receptor (HR) antagonists is an established approach to block histamine effects in
these patients.
We screened for additional beneficial effects of HR antagonists and asked whether
any of these agents would also exert growth-inhibitory effects on primary neoplastic
MCs, the human MC line HMC-1, and on two canine MC lines, C2 and NI-1.
We found that the HR1 antagonists terfenadine and loratadine suppress spontaneous
growth of HMC-1, C2, and NI-1 cells, as well as growth of primary neoplastic MCs in
all donors tested (human patients, n = 5; canine patients, n = 8). The effects of
both drugs were found to be dose-dependent (IC(50): terfenadine, 1-20 μM; loratadine,
10-50 μM). Both agents also produced apoptosis in neoplastic MCs and augmented apoptosis-inducing
effects of two KIT-targeting drugs, PKC412 and dasatinib. The other HR1 antagonists
(fexofenadine, diphenhydramine) and HR2 antagonists (famotidine, cimetidine, ranitidine)
tested did not exert substantial growth-inhibitory effects on neoplastic MCs. None
of the histamine receptor blockers were found to modulate cell-cycle progression in
neoplastic MCs.
The HR1 antagonists terfenadine and loratadine, in addition to their antimediator
activity, exert in vitro growth-inhibitory effects on neoplastic MCs. Whether these
drugs (terfenadine) alone, or in combination with KIT inhibitors, can also affect
in vivo neoplastic MC growth remains to be determined.
Copyright © 2010 ISEH - Society for Hematology and Stem Cells. Published by Elsevier
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