Inhibition of Phorbol Ester-Induced Tumor Promotion in Mice by Vitamin A Analog and Anti-inflammatory Steroid2

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Abstract
The effects of a vitamin A analog, TMMP ethyl retl-noate [or ethyl-9-(4-methoxy-2,3,6-trlmethylphenyl)-3,7-dlmeth-yl-trans-2,4,6,8-nonatetraenoate] (abbreviated Ro 10-9359), and an anti-inflammatory steroid, fluoclnolone acetonlde for 6α,9α-difluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal) (abbreviated FA), given alone or together were studied in a two-stage carclnogenesls system. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was used as the tumor promoter in a 7,12-dlmethylbenz[a]anthracene (DMBA)-inltlated mouse skin system. Two stocks of female mice, CD®-1 and Sencar, which differ in their degrees of sensitivity to skin carclnogenesis, were used. A dose-dependent inhibition of carcinogenic expression, as determined by a decreased number of papillomas per animal, was observed in each mouse stock with the use of both FA and Ro 10-9359 when given alone. When FA and Ro 10-9359 were given together, an enhanced effect on the lowering of tumor Incidence was noted. FA effectively inhibited tumor formation in the sensitive mouse stock even when the steroid was given 1 day prior to TPA treatment under conditions of unusually high doses of initiator (DMBA) and/or promoter (TPA). These results suggest that both anti-inflammatory steroids and retinolds inhibit tumor promotion and can be effectively used as a combination regimen for increased chemopreventive response.