Citral inhibits the formation of retinoic acid from retinol in mouse epidermis. Since skin-carcinogenesis is sensitive to retinoid status, and retinoic acid may be the active form of vitamin A in the epidermis, citral was tested for its ability to modulate tumor promotion in a two-stage skin-carcinogenesis study in hairless mice. The dorsal skins of female skh/hr1 mice were initiated with 0.1 mumol dimethylbenzanthracene, and tumors were promoted by twice-weekly application of 10 nmol of tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. Prior to each TPA application groups were dosed with 0, 1 mumol, or 10 mumol citral. Citral had a dose-dependent inhibitory effect on tumor-production in the TPA promoted groups. At 10 weeks of promotion the percentage of mice with tumors were 88%, 72% and 60%, for the 0, 1 and 10 mumol citral treated groups, and the numbers (mean +/- S.D.) of tumors per affected animal were 7.3 +/- 6.6, 3.9 +/- 4.2, and 3.7 +/- 3.5, respectively. At 15 weeks of promotion the tumor incidence was 96%, 96% and 84%, respectively, and the number of tumors per affected animal were 9.5 +/- 6.8, 7.2 +/- 4.6 and 4.5 +/- 3.3, respectively. Again the affected mice in the high dose citral group had significantly fewer tumors. When the study was terminated at 20 weeks of promotion all mice had at least one tumor, but the number of tumors per affected mouse were lower in the citral treated groups. These findings concur with the proposal that there is a retinoid requirement for skin tumor promotion, and establishes that anti-retinoids have potential uses as modulators of carcinogenesis.
