tretinoin and retinylidene-dimedone

The usefulness of a short-term azaserine [CAS: 115-02-6; diazoacetate serine (ester)]-rat model for the screening of retinoids (known chemopreventive agents) and the effect of two retinoids on the growth of azaserine-induced, presumptive preneoplastic foci of acinar cells were examined. At 14 days of age, male Lewis rats were each given injections of a single dose of 30 mg azaserine/kg body weight. These rats were weaned to test diets to which retinoids were added. At 4 months post initiation, pancreata were examined by quantitative stereologic methods to determine number and mean size of foci. Two phenotypically different populations of foci were observed and characterized as acidophilic or basophilic. Retinylidene dimedone and N-2-hydroxyethylretinamide decreased the number and size of the acidophilic foci but not the basophilic foci. The inhibition of growth of the acidophilic foci correlates well with the known effects of these retinoids in long-term carcinogenicity studies.

Topics: Animals; Azaserine; Dose-Response Relationship, Drug; Male; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Retinoids; Tretinoin

Sprague-Dawley rats received daily oral gavage doses of either 2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione (retinylidene dimedone; 14, 50, 150, or 330 mg/kg) or all-trans-retinoic acid (1, 4, 14, or 50 mg/kg) for 13 weeks. Rats given 50 mg/kg of all-trans-retinoic acid developed numerous long-bone fractures and became moribund during the third week of the study. Those receiving lower dosages survived until scheduled termination, but the 14 mg/kg group showed clear signs of retinoid intoxication including growth depression, anemia, serum alkaline phosphatase elevation, bone fracture, and testicular degeneration. Exposure to retinylidene dimedone did not result in any treatment-related deaths, growth depression, or histopathologic lesions, even at the highest dose, 300 mg/kg. Animals given this dosage exhibited mild anemia, equivocal evidence of bone fracture, but no increase in alkaline phosphatase activity. Retinylidene dimedone appears to be considerably less toxic than all-trans-retinoic acid.

Topics: Animals; Blood; Body Weight; Bone Diseases; Dose-Response Relationship, Drug; Female; Fractures, Bone; Male; Organ Size; Rats; Rats, Inbred Strains; Retinoids; Tretinoin

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