STRUCTURAL BASIS OF TAMOXIFEN-INDUCED RAT LIVER CANCER

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The nonsteroidal antiestrogen, tamoxifen, has found wide-spread acceptance in the treatment of all stages of breast cancer. The necessity for the long-term administration of tamoxifen and its proposed use in several chemoprevention trials has prompted a reevaluation of its ability to induce second cancers. Recently, a report (FDA Drug Bulletin 20:5, 1990) has indicated an increased incidence of liver tumors in rats exposed to a high daily dose of tamoxifen (greater than or equal to 5 mg/kg). Since tamoxifen possesses intrinsic estrogenic activity and estrogens are known tumor promoters in the rat and human, tamoxifen and five of its structural analogs will be subjected to a short and long term analysis of rat liver carcinogenesis. First, the effect of short- term (1-28 day) administration of the antiestrogens will be used to generate acute toxicity data, parent drug levels and metabolic profiles, cellular proliferation and information of P450 induction. Additionally, other potential mechanism of tumor induction will be addressed including, but not limited to, proliferation, altered carbohydrate metabolism, and altered growth factor production. The information obtained in the acute administration studies will be used to determine the dose of the antiestrogens to be employed in a 6 month, two stage- model of rat liver carcinogenesis. The endpoint in the model will be the number and volume of preneoplastic altered hepatic foci detected using 4 enzyme markers and quantitated with stereology. Both the initiation and promotion activity of these agents will be determined and a relative potency index for promotion calculated. Metabolite profiles, P450 induction, and cellular proliferation will be determined after this chronic 6 month exposure to the antiestrogens. The dose level for the 15 month tumor study will be derived from these data. The rank order potency for the development of hepatocellular carcinoma by tamoxifen, mestranol, and the 5 tested antiestrogens will be compared with that obtained in the 6-month promotion study and the short-term tests to assess which short term test correlates with tumor formation. This information will be valuable to screen other antiestrogen promoters of liver carcinogenesis. The structural basis for tamoxifen-induced liver tumors will be determined using several analog designed to limit isomerization and/or metabolism. These chemical considerations may be important to prevent liver carcinogenesis. The principal current concern about the use of tamoxifen in the normal population is the induction of liver tumors. This proposal seeks to provide essential laboratory data to address these concerns.