Retinoids are effective chemopreventive agents in a variety of chemically induced epithelial cancers in experimental animals; however, little is known as to the effect of retinoids in liver cancer. Thus, studies will be conducted to determine if the retinoids afford protection against hepatocellular carcinoma. The retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), was chosen because it is highly effective against breast and bladder cancer and has low toxicity. In addition, high levels of the retinoid are attained in the liver as well as mammary gland. In studying the effectiveness of 4-HPR in liver carcinoma and its possible clinical application, it becomes important to study the individual variation in the response of liver cancer to 4-HPR. Thus, 4-HPR inhibition of liver carcinoma will be examined in five inbred strains of mice. Pharmacogenetic studies of 4-HPR metabolism will be conducted and pharmacokinetic differences between the strains will be correlated with differences in response to 4-HPR relative to liver cancer induction. If all strains respond identically, then similarities in the pharmacokinetic data will help to identify what factors may be important in chemoprevention. If 4-HPR is ineffective in inhibiting liver cancer in these strains, then a comparison of the pharmacokinetics in liver, breast, and bladder will provide insight as to why the retinoid failed. Retinoid metabolism studies will be performed in isolated hepatocytes to provide quantitative information of the biochemical fate of 4-HPR in the liver and to identify divergent pathways of liver metabolism between strains. The results of this comparison may indicate the compound responsible for 4-HPR action and may also provide evidence on mechanisms of retinoid action in the liver. Lastly, these studies may indicate what trait is responsible for the pharmacogenetic variation in 4-HPR response.
| Hultin, T A; Filla, M S; McCormick, D L (1990) Distribution and metabolism of the retinoid, N-(4-methoxyphenyl)-all-trans-retinamide, the major metabolite of N-(4-hydroxyphenyl)-all-trans-retinamide, in female mice. Drug Metab Dispos 18:175-9 |
