PHORBOL ESTER-INDUCED LEUKOTRIENE BIOSYNTHESIS AND TUMOR PROMOTION INMOUSE EPIDERMIS

In mouse skin in vivo the irritant and hyperplasiogenic tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) strongly increased the epi dermal content of the cysteinyl leukotrienes LTC(4), LTD(4) and LTE(4) , but not of leukotriene LTB(4). This effect was completely suppressed by the selective leukotriene biosynthesis inhibitor MK-886, Intragast ric administration of MK-886 prevented phorbol ester-induced ear edema , but not epidermal hyperproliferation and tumor promotion. These data indicate that leukotrienes are involved in the pro-inflammatory effec ts of the phorbol ester, whereas its hyperproliferative and tumor-prom oting activities do not depend on 5-lipoxy-genase-catalyzed leukotrien e formation, This action differs from several non-selective inhibitors of lipoxygenases that were found to inhibit tumor promotion in initia ted mouse skin.