McCormick D L, Bagg B J, Hultin T A
Life Sciences Research, IIT Research Institute, Chicago, Illinois 60616.
Cancer Res. 1987 Nov 15;47(22):5989-93.
The activity of dietary and topical administration of three retinoids, all-trans-retinoic acid, 13-cis-retinoic acid, and N-(4-hydroxyphenyl)retinamide (4-HPR), as promoters of skin tumor induction in SENCAR mice was studied. When administered as dietary supplements at their maximum tolerated dose levels, all three retinoids promoted tumorigenesis in mice initiated with a single topical dose of 5 micrograms 7,12-dimethylbenz(a)anthracene. Maximal promoting activity was observed with dietary 13-cis-retinoic acid; dietary 4-HPR was significantly less active than was either isomer of retinoic acid. When administered via topical application, all-trans- and 13-cis-retinoic acids both promoted skin tumor induction; 4-HPR did not. HPLC analysis of skin samples from mice receiving dietary 4-HPR showed the parent compound and six metabolites; these metabolites were not found in the skin of mice receiving topical 4-HPR exposure, although 4-HPR itself was present. These data indicate that skin tumor promotion can be induced by systemic administration as well as topical application of the all-trans- and 13-cis-retinoic acids. Substitution of a 4-hydroxyphenylamide terminal group results in a significant reduction in promoting activity. 4-HPR appears to require metabolic activation for tumor promoting activity; this metabolism does not occur in the skin following topical application, but is observed following systemic exposure.
研究了三种维甲酸（全反式维甲酸、13-顺式维甲酸和N-(4-羟基苯基)维甲酰胺（4-HPR））经饮食和局部给药作为SENCAR小鼠皮肤肿瘤诱导促进剂的活性。当以其最大耐受剂量水平作为饮食补充剂给药时，所有三种维甲酸均促进了单次局部给予5微克7,12-二甲基苯并(a)蒽启动的小鼠肿瘤发生。饮食给予13-顺式维甲酸时观察到最大促进活性；饮食给予4-HPR的活性明显低于维甲酸的任何一种异构体。通过局部应用给药时，全反式和13-顺式维甲酸均促进皮肤肿瘤诱导；4-HPR则不然。对接受饮食给予4-HPR的小鼠皮肤样本进行的HPLC分析显示有母体化合物和六种代谢产物；接受局部给予4-HPR暴露的小鼠皮肤中未发现这些代谢产物，尽管4-HPR本身存在。这些数据表明，全反式和13-顺式维甲酸经全身给药以及局部应用均可诱导皮肤肿瘤促进作用。4-羟基苯基酰胺末端基团的取代导致促进活性显著降低。4-HPR似乎需要代谢激活才能发挥肿瘤促进活性；这种代谢在局部应用后皮肤中不发生，但在全身暴露后可观察到。
