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Structure-Activity Relationships among Various Retinoids and Their Ability to Inhibit Neoplastic Transformation and to Increase Cell Adhesion in the C3H/10T CL8 Cell Line¹

Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, New York 14263

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/10T clone 8 mouse fibroblast line (System 1); and (b) their ability to increase the degree of adhesion of C3H/10T 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 retinoic acid isomers in the C3H/10T clone 8 system is paradoxical and may provide important information on requirements for their activation and/or transport.

¹ Supported in part by USPHS Grant CA-25484.

Received 11/19/79. Accepted 6/ 3/80.