dinoprost and Papilloma

When applied to NMRI mouse skin in vivo, phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and 12-O-retinoylphorbol-13-acetate (RPA) have been found to induce two early waves of prostaglandin E2 (PGE2) synthesis after 15 and 90 min and a delayed accumulation of prostaglandin F2 alpha (PGF2 alpha) after 2 h. With respect to PGF2 alpha formation different activities of both agents were observed, in that TPA but not RPA induced additional PGF2 alpha waves after 4 and 17 h. Functionally, PGE2 was previously shown to be an endogenous mediator of the TPA- or RPA-induced epidermal hyperproliferation and hyperplasia. A functional role of PGF2 alpha could be attributed to the post-initiation stages of tumor development in initiated mouse skin, i.e. the conversion stage (stage I of tumor promotion) elicited by two TPA applications and the promotion stage (stage II of promotion) brought about repetitive RPA treatments. PGF2 alpha, appearing as one distinct biosynthetic wave 3-4 h after TPA application seems to be critically involved in the conversion steps since (i) inhibition of its accumulation by indomethacin led to an inhibition of tumor formation, (ii) the inhibitory effect of indomethacin could be reversed by PGF2 alpha and (iii) RPA was not able to give rise to the accumulation of PGF2 alpha 4 h after application as obtained by TPA treatment. Moreover, RPA-induced promotion of DMBA- and TPA-treated mouse skin was inhibited by indomethacin. The inhibitory effect of indomethacin on papilloma formation was again reversed by PGF2 alpha treatment concomitant with RPA.

Topics: Animals; Cocarcinogenesis; Dinoprost; Dinoprostone; Epidermis; Indomethacin; Mice; Papilloma; Phorbol Esters; Skin Neoplasms; Tetradecanoylphorbol Acetate

TPA promotion of skin tumors in mice can be modified by application of various prostaglandins or their precursors. The effects depend on the particular prostaglandin used: PGF2alpha enhances promotion, whereas PGE1 consistently inhibits promotion. Time of application of the prostaglandin with respect to TPA determines whether PGE2 enhances or inhibits. Dose-dependent inhibition was observed for arachidonic acid. The prostaglandins alone were unable to elicit tumors in initiated mice.

Topics: Animals; Arachidonic Acid; Carcinogens; Cell Transformation, Neoplastic; Cocarcinogenesis; Dinoprost; Dinoprostone; Female; Mice; Mice, Inbred SENCAR; Oxytocics; Papilloma; Prostaglandins; Skin Neoplasms; Tetradecanoylphorbol Acetate