Irritant diterpene ester promoters of mouse skin: contributions to etiologies of environmental cancer and to biochemical mechanisms of carcinogenesis.

One of the most advanced experimental models for investigations of the metabolic fate and of mechanisms of action of initiators and promoters at the cell and/or the molecular level is the three-stage initiation/promotion/progression model of carcinogenesis in mouse skin. In etiologic investigation by experimental analyses of local lifestyle-associated esophageal cancer on the Caribbean island of Curacao, based on this model initiators of the solitary carcinogenic PAH type and promoters of the cocarcinogenic diterpene ester (tigliane) type were suggested as putative principal risk factors. In metabolic investigations it was shown that 7,12-dimethylbenz(a)anthracene (DMBA) requires metabolic activation to yield "ultimate initiator(s)," whereas TPA and its diterpene ester congeners are "ultimate promoters" themselves. Yet naturally occurring "cryptic" forms of diterpene ester irritants and promoters require metabolic activation. To show structure/activity relationships, selected new diterpene structures of the tigliane, ingenane, and daphnane types and their irritant and promoting activities in mouse skin are presented in this paper. Common structural features of the diterpene moieties relevant for interaction with cellular receptors are identified. Synthetic modification of the ester moieties reveals highly unsaturated analogs of 12-O-tetradecanoylphorbol-13-acetate (TPA) allowing for dissection of the promotional stage in the mouse skin model in two operationally defined substages, PI and PII. In many tissues and cells, TPA and congeners induce various different biological effects, e.g., phospholipid synthesis is stimulated in epidermis, virus synthesis is stimulated in human lymphoblastoid cell lines carrying latent genomes of Epstein-Barr virus (EBV), and prostaglandin E2 is rapidly released from mouse peritoneal macrophages. Altogether a remarkable biological and biochemical pleiotropism of diterpene ester promoters is indicated. In investigations of the molecular mechanism of action of diterpene esters, non-promoting short chain phorbol esters, such as phorbol-12,13-dipropionate (PDPr) were shown to inhibit diterpene ester-induced promotion in vivo. In radioligand assays employing (20-3H)PDPr as well as (20-3H)TPA, specific binding to the particulate fractions of mouse skin and other mouse organs, including the brain, is seen. Inhibition of specific binding by a series of diterpene esters is correlated with their irritant and promoting activities.(ABSTRACT TRUNCATED AT 400 WORDS)