STRUCTURAL BASIS OF TAMOXIFEN-INDUCED RAT LIVER CANCER

非类固醇抗雌激素他莫昔芬已经发现了广泛的 接受所有阶段的乳腺癌治疗。这个 三苯氧胺长期给药的必要性及建议 在几个化学预防试验中的使用促使对其进行重新评估 诱发第二次癌症的能力。最近，一份报告(FDA药品公告) 20：5,1990)表明大鼠肝脏肿瘤的发病率增加 暴露于大剂量的三苯氧胺(大于或等于5 Mg/kg)。由于他莫昔芬具有内在的雌激素活性， 雌激素是已知的肿瘤促进剂，在大鼠和人类中，他莫昔芬和 它的五个结构类似物将受到短和长的 大鼠肝癌发生的术语分析。首先，做空的影响- 长期(1-28天)服用抗雌激素将用于 生成急性毒性数据、母体药物水平和代谢情况， 细胞增殖和P450诱导的信息。另外， 其他潜在的诱发肿瘤的机制也将被提及。 包括但不限于增殖、改变的碳水化合物 新陈代谢，改变生长因子的产生。这些信息 在急性给药研究中获得的结果将被用来确定 在6个月内分两个阶段使用的抗雌激素剂量- 大鼠肝癌变模型。模型中的端点将为 癌前病变肝内病灶数目和体积的检测 采用4种酶标记物，体视学定量。这两个 将确定这些代理的发起和推广活动，并 计算出的晋升相对效力指数。代谢物图谱， P450的诱导，细胞增殖将在此之后确定。 长期接触抗雌激素药物6个月。的剂量水平 15个月的肿瘤研究将从这些数据中得出。排名顺序 他莫昔芬在肝细胞癌发生中的作用 甲孕醇和5种测试的抗雌激素将与之进行比较 在为期6个月的推广研究和短期测试中获得 评估哪种短期测试与肿瘤形成相关。这 这些信息将对筛选其他抗雌激素促进剂有价值。 肝癌的发生。他莫昔芬诱导肝损伤的结构基础 将使用几个旨在限制肿瘤的类似物来确定 异构化和/或代谢。这些化学方面的考虑可能是 对预防肝癌的发生有重要作用。主流 对正常人群中使用他莫昔芬的担忧是 诱发肝脏肿瘤。这项提案旨在提供必要的 实验室数据来解决这些担忧。

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.