The
growth factor- and
phorbol ester-inducible
prostaglandin H synthase (PGHS)-2 has been found to be constitutively overexpressed in epidermal
tumors generated by the initiation-promotion protocol in murine skin, whereas the expression of PGHS-1 does not change under these conditions. In this paper we report the intra-
tumor distribution of the aberrantly expressed
PGHS-2 and the
cancer chemopreventive activity of a specific
PGHS-2 inhibitor. By immunohistochemical methods using
isoenzyme-specific
antibodies, we found that the PGHS-1
protein was expressed in keratinocytes and Langerhans cells dispersed throughout the epithelial part of
papillomas and
squamous cell carcinomas and in inflammatory infiltrates occasionally seen in these
tumors. A uniform pattern of
PGHS-2 expression was observed in the basal keratinocytes of
papillomas and in the follicular keratinocytes of
carcinomas. In addition, Langerhans cells as well as
tumor-associated inflammatory infiltrates exhibited PGHS-2-specific immunoreactivity. PGHS-2-catalyzed
prostaglandin synthesis stimulated by the
phorbol ester 12-O-tetradecanoylphorbol-13
acetate (TPA) in mouse epidermis in vivo was dose-dependently suppressed by
topical administration of
SC-58125, a specific
PGHS-2 inhibitor. TPA-induced
edema formation, epidermal
DNA synthesis, and mitotic activity were not impaired by
SC-58125 applied at a dose that inhibited TPA-induced
prostaglandin E2 synthesis. However, the repetitive epicutaneous administration of
SC-58125 substantially and significantly suppressed
papilloma development. Malignant progression of
papillomas was slightly retarded by the
drug. These results indicate that aberrant expression of
PGHS-2 in epidermal
tumors may be a relevant target for prevention of epidermal
cancer development in experimental animals and that the PGHS-2-specific inhibitor
SC-58125, which is a potent inhibitor of
tumor promotion in mouse skin, may be important for
cancer chemoprevention in humans as well.