retinylidene-dimedone and Cell-Transformation--Neoplastic

Various natural and synthetic retinoids have been studied for their activity in two biological systems: (a) their activity as inhibitors of methylcholanthrene-induced neoplastic transformation in the C3H/10T1/2 clone 8 mouse fibroblast line (System 1); and (b) their ability to increase the degree of adhesion of C3H/10T1/2 clone 8 cells to a plastic substrate (System 2). These activities were then compared with their known activity in maintaining epithelial differentiation (System 3). With the notable exception of retinoic acid and 13-cis-retinoic acid, which were inactive in Systems 1 and 2, an excellent correlation was observed between activities in Systems 1 and 3 for retinyl acetate, N-(4-hydroxyphenyl)retinamide, retinylidene dimedone, N-ethylretinamide, and N-benzoylretinylamine. Compounds shown to be inactive in System 1 had little or no activity in System 2. However, the ability of retinoids to cause increased adhesion could not be correlated with Systems 1 or 3 in all cases. For instance, retinyl acetate was highly active in Systems 1, 2, and 3, whereas retinylidene dimedone was highly active in Systems 1 and 3 but weakly active in System 2. Conversely, N-(4-hydroxyphenyl)retinylamide was highly active in Systems 1 and 3 but caused a decrease in System 2. The lack of activity of 3 but caused a decrease in System 2. The lack of activity of retinoic acid isomers in the C3H/10T1/2 clone 8 system is paradoxical and may provide important information on requirements for their activation and/or transport.

Topics: Amides; Animals; Cell Adhesion; Cell Line; Cell Transformation, Neoplastic; Diterpenes; Fenretinide; Isotretinoin; Methylcholanthrene; Mice; Neoplasms, Experimental; Retinoids; Retinyl Esters; Structure-Activity Relationship; Tretinoin; Vitamin A

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Biotransformation; Carcinogens; Cell Transformation, Neoplastic; Female; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Organ Culture Techniques; Retinoids; Vitamin A

The mouse mammary gland in whole-organ culture, an in vitro system that is capable of alveolar development, differentiation, involution, and oncogenic transformation, has been used to examine the effects of the retinoid 2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione (retinylidene dimedone) on epithelial transformation by a low concentration (10 nM) of the carcinogen 7,12-dimethylbenz[a]anthracene. The retinoid significantly prevented mammary gland transformation only when administered after the carcinogen. In addition, the phenotypes of the early transformed state of the mammary gland were suppressed for 20 days after removal of the retinoid. The retinoid was effective during both mammary alveolar development and regression in culture at concentrations as low as 1 nM, and itself had no significant transforming or cytotoxic activity. Mammary glands treated with both the carcinogen and the retinoid resembled, at the microscopic level, those given the solvent (dimethyl sulfoxide) only. The mouse mammary gland in whole-organ culture provides a promising model system in which to study the actions by which retinoids prevent and suppress the chemical transformation in vitro and oncogenesis in vivo of epithelial cells in general and of mammary gland in particular. The present findings support the suggestion that a search for suitable retinoids as chemopreventive agents against human breast cancer is warranted. This model system may be useful as initial indicator in that search.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Cell Transformation, Neoplastic; Female; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Organ Culture Techniques; Retinoids; Vitamin A