Studies on mechanism of action of anti-tumor-promoting agents: their specificity in two-stage promotion.

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Abstract
The effects of fluocinolone acetonide (FA), retinoic acid (RA) and tosylphenylalanine chloromethyl ketone (TPCK) on 2-stage promotion after 7,12-dimethylbenz[a]anthracene (DMBA) initiation in female Sencar mice were investigated. The 2-stage promotion protocol was achieved by twice weekly applications of 2 .mu.g of 12-O-tetradecanoylphorbol 13-acetate (TPA) for 2 wk (stage I) followed by twice weekly applications of mezerein for 18 wk (stage II). Separately, stage I and II do not cause any tumors to develop after DMBA initiation. FA was a potent inhibitor of stages I and II, but to a greater degree for stage I than for stage II. RA was ineffective in stage I but was a potent inhibitor of stage II; TPCK specifically inhibited stage I but not stage II. FA and TPCK effectively counteract the appearance of the dark basal keratinocytes; RA has no effect. Additional evidence for the importance of dark basal keratinocytes in stage I of promotion is provided. Most of the other biochemical and morphological responses normally associated with promotion (such as polyamines) are probably actually associated with stage II of promotion.