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 alpha-difluoromethylornithine (DFMO) in the drinking water on 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation was determined. Administration of 13-cis-RA in the diet and DFMO in the drinking water was started 1 week and 2 days before the first TPA application to the dimethylbenz[a]anthracene-initiated skin of either female CD-1 or SENCAR mice, respectively. Dietary 13-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-RA doses were 25, 30, 22, 28 and 25 respectively at 18 weeks of promotion treatment and at all doses 100% of the mice bore papillomas. However, dietary 13-cis-RA dramatically reduced the size of skin tumor promoted with TPA. 13-Cis-RA at doses of 5, 50, 100 and 200 mg/kg diet inhibited skin papillomas (greater than 4 mm diameter) per mouse by 28, 55, 76 and 93%, respectively. Retinoid treatment did not affect body weight gains and the survival was more than 80% in all groups. In accord with our previous findings, DFMO when given in drinking water, was a very effective inhibitor of mouse skin tumor promotion by TPA; DFMO at 0.25% concentration inhibited the number of papillomas by 50%. Inhibition of skin tumor promotion by combined treatments with dietary 13-cis-RA (100 mg/kg) and DFMO (0.25%) in the drinking water was possibly additive. The retinoid and DFMO preclude TPA-increased ornithine decarboxylase (ODC) activity and the accumulation of putrescine by differential effects on ODC, an enzyme associated with skin tumor promotion by TPA.
D000818:Animals; D004032:Diet; D000518:Eflornithine; D005260:Female; D015474:Isotretinoin; D051379:Mice; D008815:Mice, Inbred Strains; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000032:analysis; D010212:Papilloma / Q000139:chemically induced / Q000517:prevention & control*; D012867:Skin / Q000201:enzymology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate; D014212:Tretinoin / Q000494:pharmacology*
D014212:Tretinoin; D009952:Ornithine; D009955:Ornithine Decarboxylase; D015474:Isotretinoin; D013755:Tetradecanoylphorbol Acetate; D000518:Eflornithine