Effects of antihistamines on phorbol ester tumor promotion and vascular permeability changes.
Substantial evidence suggests that inflammation is an essential component of the phorbol ester tumor promotion stage of multistage carcinogenesis in mouse skin. In order to understand better the significance of this relationship, studies were directed at identifying the principal mediators of the vascular permeability component of inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Antihistamines and inhibitors of arachidonic acid metabolism were compared with respect to their anti-inflammatory activity and the correlation of this parameter with their effect on tumor promotion. The H1 histamine receptor antagonist, diphenhydramine, suppressed TPA-induced vascular leakage by 25 and 50% at topical doses of 0.342 mumol (100 micrograms) and 0.856 mumol (250 micrograms) respectively. In initiated mice, these same doses inhibited papilloma development by 40 and 75%. Inhibition of tumors was also observed when diphenhydramine was given orally. The H2 antagonist, cimetidine, which could only be supplied orally, had little effect on either TPA-induced vascular permeability or promotion. The lipoxygenase inhibitor nordihydroguaiaretic acid also suppressed vascular permeability and has been reported to inhibit papilloma development. The cyclooxygenase inhibitor indomethacin, however, has no effect on TPA-induced vascular permeability. Collectively, these data suggest that the increased vascular leakage observed with TPA contributes to tumor development and that this event is mediated by both the H1 histamine receptors and one or more of the lipoxygenase products of arachidonic acid.
Fischer
S M
SM
University of Texas, M.D. Anderson Cancer Center, Smithville 78957.
Patrick
K E
KE
Patamalai
B
B
Slaga
T J
TJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002927:Cimetidine / Q000494:pharmacology*; D004155:Diphenhydramine / Q000494:pharmacology*; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D010212:Papilloma / Q000139:chemically induced* / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
D015127:9,10-Dimethyl-1,2-benzanthracene; D009637:Masoprocol; D002927:Cimetidine; D004155:Diphenhydramine; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin