Showing papers by "Michael B. Sporn published in 1976"

Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids).

Abstract: An approach to chemoprevention of common forms of epithelial cancer, during the period of preneoplasia, is described Vitamin A and its synthetic analogs (retinoids) are potent agents for control of cell differentiation in many epithelial tissues Direct effects of retinoids on normal and preneoplastic cell differentiation can be measured in organ culture In experimental animals, deficiency of dietary retinoids enhances susceptibility to chemical carcinogenesis Natural retinoids, fed at high dietary levels, have some ability to prevent chemical carcinogenesis in epithelial tissues of bronchi, trachea, stomach, uterus, and skin of experimental animals However, natural retinoids have limited usefulness for chemoprevention of cancer because of inadequate tissue distribution and excessive toxicity Synthetic retinoids have been made and shown to be more potent and less toxic for prevention of cancer in animals Several structural modifications of the ring and terminal portions of the retinoid molecule have significant biological activity; modification of the side chain has been more difficult The potential future usefulness of this approach to cancer prevention in man will depend on further synthetic modification of the retinoid molecule

Approaches to Prevention of Epithelial Cancer during the Preneoplastic Period

Abstract: The development of epithelial cancer is a disease process that takes many years to reach its final, invasive stage in humans. This disease process has the potential to be controlled by physiological or pharmacological means during its preneoplastic stages. Mechanisms whereby the progression of preneoplastic lesions can be stabilized, arrested, or reversed are discussed. Pharmacological enhancement of such mechanisms by synthetic vitamin A analogs (retinoids) offers a possible means for prevention of invasive epithelial cancer.

Relationships between structure and activity of retinoids

Abstract: Structure-function relationships of 19 retinoids were studied in three in vitro systems in defined, serum-free medium. These systems measure effects on differentiation and growth, as well as toxic effects. The ring, side chain, and polar terminal group of natural retinoids all may be modified synthetically to yield highly active compounds. Several retinoid ethers were found to be significantly less toxic than the corresponding carboxylic acids or alcohols.

Inhibition of 7,12-Dimethylbenz(a)anthracene-induced Mammary Carcinogenesis by Retinyl Acetate

Abstract: The administration of 2.5 mg retinyl acetate daily in the diet to female Sprague-Dawley rats beginning 7 days after the intragastric instillation of either 2.5, 5, or 15 mg 7,12-dimethylbenz(a)anthracene (CMBA) resulted in a reduction in the incidence of benign mammary tumors of 37, 30, and 31%, respectively. An equally significant reduction in the number of tumors was also evident. Although no difference was noted in the percentage incidence of mammary adenocarcinomas between the placebo and 2.5 mg retinyl acetate-treated groups at the 2.5-mg DMBA level, the percentage incidence was reduced by 52 and 39% in these groups at the 5- and 15-mg DMBA dose. Furthermore, the number of adenocarcinomas was also significantly reduced. Although both the percentage incidence and number of tumors were reduced by treatment with 1 mg retinyl acetate, these differences were not statistically significant. Liver histology and liver function tests of rats of the retinyl acetate groups did not differ from that of the control group. Similarly, the estrus cycle of treated animals did not differ from that of control rats. These data indicate that relatively large doses of retinyl acetate significantly inhibit the development of DMBA-induced mammary adenocarcinomas and benign tumors. Furthermore, the suppression of mammary tumorigenesis is apparently not the result of an alteration in either the metabolism of DMBA or estrogen nor to an inhibition of tumor growth resulting from retinyl acetate toxicity. The inhibitory effect of retinyl acetate may be related to the effect of retinoids on epithelial cell differentiation and/or reversal of carcinogen-induced anaplasia.

Organ Culture of Normal and Carcinogen-treated Rat Bladder

Abstract: A system for organ culture of rat bladder in defined medium, without serum, is described. Transitional epithelial morphology of normal bladder was well maintained in Waymouth's Medium MB 752/1, while Ham's Medium F12 caused marked epithelial hyperplasia. Hyperplastic epithelial states induced by in vivo administration of the carcinogen, N -methyl- N -nitrosourea, were well maintained in vitro during organ culture in Medium MB 752/1. The combination of hydrocortisone and insulin markedly inhibited the proliferative response of normal bladder epithelium grown in Medium F12.