It has become evident that
retinoids control differentiation, embryonal development, and
tumorigenesis. In animal models, skin
tumorigenesis has been shown to be prevented by
retinoids, which in this organ function as antitumor promoters in the two-stage system using
7,12-dimethylbenz(a)anthracene (DMBA) as the initiator, and 12-tetradecanoyl-phorbol-13-acetate (TPA) as
tumor promoter. Even though pharmacological doses applied topically appear to inhibit
tumor formation, we found that
papilloma and
keratoacanthoma growth required physiological concentrations of
retinoic acid and that
vitamin A deficiency was even more effective than excess
retinoid in inhibiting SENCAR mouse skin
tumorigenesis. In human beings,
oral administration of
retinoic acid after
tumor resection was effective in inhibiting the appearance of new
tumors on the skin of four patients with
Xeroderma Pigmentosum, and was effective in preventing new primary
tumor formations in patients treated for
head and neck cancer. The newly-discovered
nuclear receptors for
retinoic acid function as transcriptional activators for several genes. In patients with
acute promyelocytic leukemia presenting with a reciprocal translocation of chromosome 17 to chromosome 15, the breakpoint has been identified in the
retinoic acid receptor alpha gene, which forms a fusion gene with a new gene termed myl, on chromosome 15. Treatment of the patients with
retinoic acid causes complete remission of the APL. It also appears to generate cells that do not bear the translocation. Therefore,
retinoids may well function as modulators of
carcinogenesis both at the promotion level as well as by causing differentiation of neoplastically transformed cells.