H1-receptor antagonists terfenadine and loratadine inhibit spontaneous growth of neoplastic mast cells.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hadzijusufovic
Emir
E
Department for Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria.
Peter
Barbara
B
Gleixner
Karoline V
KV
Schuch
Karina
K
Pickl
Winfried F
WF
Thaiwong
Tuddow
T
Yuzbasiyan-Gurkan
Vilma
V
Mirkina
Irina
I
Willmann
Michael
M
Valent
Peter
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002415:Cats; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000069439:Dasatinib; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D017336:Loratadine / Q000494:pharmacology*; D034801:Mastocytoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D016593:Terfenadine / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D039563:Histamine H1 Antagonists, Non-Sedating; D011743:Pyrimidines; D013844:Thiazoles; D017336:Loratadine; D016593:Terfenadine; D019009:Proto-Oncogene Proteins c-kit; D053148:Caspase 3; D019311:Staurosporine; C059539:midostaurin; D000069439:Dasatinib