Multiple mechanisms: the example of vitamin A.
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.
De Luca
L M
LM
National Cancer Center Institute, Bethesda, Maryland 20892.
D000293:Adolescent; D000328:Adult; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D012176:Retinoids / Q000494:pharmacology / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000150:complications / Q000517:prevention & control*; D014801:Vitamin A / Q000494:pharmacology* / Q000627:therapeutic use*; D014983:Xeroderma Pigmentosum / Q000150:complications
D016588:Anticarcinogenic Agents; D012176:Retinoids; D014801:Vitamin A