Nonpromoting 12-deoxyphorbol 13-esters inhibit phorbol 12-myristate 13-acetate induced tumor promotion in CD-1 mouse skin.
Prostratin and 12-deoxyphorbol 13-phenylacetate (dPP) form a new class of protein kinase C activators of unique biological activity. Although they bind to and activate protein kinase C, in mouse skin they either fail to induce typical phorbol ester (PMA) effects (e.g., hyperplasia) or induce only partial response (e.g., inflammation). Furthermore, pretreatment with these agents inhibits a range of PMA induced effects (acute and chronic hyperplasia, inflammation, etc.) These observations suggested that prostratin and dPP would function as inhibitors of phorbol ester tumor promotion. Here we verify that prediction. We report that both compounds reduced both the average number of papillomas and the tumor incidence in a tumor promotion schedule in CD-1 mouse skin, in which each PMA application was preceded by 12-deoxyphorbol 13-monoester pretreatment. The highest dose of prostratin used (2.56 mumol or 1 mg/pretreatment) caused a 96% (23-fold) reduction in the average number of papillomas with a decrease of tumor incidence from 97 to 40%. The highest dose of dPP used (21.4 nmol or 10 micrograms/pretreatment) induced an 86% (7-fold) reduction in the average number of papillomas with a 53% reduction of tumor incidence from 100 to 47%. The inhibitory effect was dose dependent. The dose causing 50% inhibition was 11 nmol/pretreatment for prostratin and 0.8 nmol/pretreatment for dPP. Maximal inhibition of tumor promotion was accompanied by a block of epidermal hyperplasia; however, significant inhibition of tumor induction was observed at doses without any apparent effect on the PMA induced hyperplasia.
Szallasi
Z
Z
Molecular Mechanisms of Tumor Promotion Section, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Krsmanovic
L
L
Blumberg
P M
PM
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D051379:Mice; D010212:Papilloma / Q000139:chemically induced / Q000517:prevention & control*; D010703:Phorbol Esters / Q000008:administration & dosage / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate
D010703:Phorbol Esters; D015127:9,10-Dimethyl-1,2-benzanthracene; C029704:12-deoxyphorbolphenylacetate; C070999:prostratin; D013755:Tetradecanoylphorbol Acetate