Modulation of mouse skin tumor promotion by dietary 13-cis-retinoic acid and {alpha}-difluoromethylornithine

The effects of dietary supplementation of 13-cis-retinoic acid(13-cis-RA) and -difluoromethylornithine (DFMO) in the drinkingwater on 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotedskin tumor formation was determined. Administration of 13-cis-RAin the diet and DFMO in the drinking water was started 1 weekand 2 days before the first TPA application to the dimethylbenz[a]anthracene-initiatedskin of either female CD-I or SENCAR mice, respectively. Dietary13-cis-RA failed to inhibit both the tumor yield and the incidence;papillomas per mouse at 0, 5, 50, 100 and 200 mg/kg diet 13-cis-RAdoses were 25, 30, 22, 28 and 25 respectively at 18 weeks ofpromotion treatment and at all doses 100% of the mice bore papillomas.However, dietary 13-cis-RA dramatically reduced the size ofskin tumor promoted with TPA. 13-cis-RA at doses of 5, 50, 100and 200 mg/kg diet inhibited skin papillomas (> 4 mm diameter)per mouse by 28, 55, 76 and 93%, respectively. Retinoid treatmentdid not affect body weight gains and the survival was more than80% in all groups. In accord with our previous findings, DFMOwhen given in drinking water, was a very effective inhibitorof mouse skin tumor promotion by TPA; DFMO at 0.25% concentrationinhibited the number of papillomas by 50%. Inhibition of skintumor promotion by combined treatments with dietary 13-cis-RA(100 mg/kg) and DFMO (0.25%) in the drinking water was possiblyadditive. The retinoid and DFMO preclude TPA-increased ornithinedecarboxylase (ODC) activity and the accumulation of putrescineby differential effects on ODC, an enzyme associated with skintumor promotion by TPA.