Eicosanoids and multistage carcinogenesis in NMRI mouse skin: role of prostaglandins E and F in conversion (first stage of tumor promotion) and promotion (second stage of tumor promotion)

When applied to NMRI mouse skin in vivo, phorbol esters suchas 12-O-tetradecanoylphorbol-13-acetate (TPA) and 12-O-retinoylphorbol-13-acetate(RPA) have been found to induce two early waves of prostaglandinE₂ (PGE₂) synthesis after 15 and 90 min and a delayed accumulationof prostaglandin F₂ (PGF₂) after 2 h. With respect to PGF₂ formationdifferent activities of both agents were observed, in that TPAbut not RPA induced additional PGF waves after 4 and 17 h. Functionally,PGE₂ was previously shown to be an endogenous mediator of theTPA- or RPA-induced epidermal hyperproliferation and hyperplasia.A functional role of PGF could be attributed to the post-initiationstages of tumor development in initiated mouse skin, i.e. theconversion stage (stage I of tumor promotion) elicited by twoTPA applications and the promotion stage (stage II of promotion)brought about repetitive RPA treatments. PGF₂, appearing asone distinct biosynthetic wave 3–4 h after TPA applicationseems to be critically involved in the conversion steps since(i) inhibition of its accumulation by indomethacin led to aninhibition of tumor formation, (ii) the inhibitory effect ofindomethacin could be reversed by PGF₂ and (iii) RPA was notable to give rise to the accumulation of PGF₂ 4 h after applicationas obtained by TPA treatment. Moreover, RPA-induced promotionof DMBA- and TPA-treated mouse skin was inhibited by indomethacin.The inhibitory effect of indomethacin on papilloma formationwas again reversed by PGF treatment concomitant with RPA.