Anzano M A, Byers S W, Smith J M, Peer C W, Mullen L T, Brown C C, Roberts A B, Sporn M B
Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892.
Cancer Res. 1994 Sep 1;54(17):4614-7.
We show that 9-cis-retinoic acid (9cRA) is a potent inhibitor of mammary carcinogenesis induced by N-nitroso-N-methylurea in Sprague-Dawley rats. Rats were first treated with a single dose of N-nitroso-N-methylurea (50 mg/kg body weight) and then fed non-toxic levels of 9cRA (120 or 60 mg/kg of diet). 9cRA was highly effective in reducing tumor incidence, average number of tumors per rat, and average tumor burden, as well as extending tumor latency. The combination of 9cRA with low levels of tamoxifen (TAM; fed at either 1.0 or 0.5 mg/kg of diet) was particularly effective; addition of 9cRA to a TAM regimen doubled the number of animals that were tumor-free at autopsy and significantly diminished tumor number and tumor burden. For suppression of carcinogenesis in vivo, 9cRA was much more potent than all-trans-retinoic acid, both as a single agent or in combination with TAM, although both retinoids had equivalent inhibitory effects on DNA synthesis in cultured human breast cancer cell lines. Both 9cRA and all-trans-retinoic acid induce the expression of the adhesion molecule, E-cadherin, in the SK-BR-3 cell line. We suggest that clinical evaluation of the combination of 9cRA and TAM, either for chemoprevention or for adjuvant therapy, should be considered.
我们发现9-顺式视黄酸（9cRA）是N-亚硝基-N-甲基脲诱导的Sprague-Dawley大鼠乳腺癌发生的有效抑制剂。大鼠首先接受单剂量的N-亚硝基-N-甲基脲（50毫克/千克体重）处理，然后喂食无毒水平的9cRA（120或60毫克/千克饲料）。9cRA在降低肿瘤发生率、每只大鼠的平均肿瘤数量和平均肿瘤负荷以及延长肿瘤潜伏期方面非常有效。9cRA与低剂量他莫昔芬（TAM；以1.0或0.5毫克/千克饲料喂食）联合使用特别有效；在TAM方案中添加9cRA使尸检时无肿瘤动物数量增加一倍，并显著减少肿瘤数量和肿瘤负荷。对于体内致癌作用的抑制，无论是作为单一药物还是与TAM联合使用，9cRA都比全反式视黄酸有效得多，尽管这两种类视黄醇对培养的人乳腺癌细胞系中的DNA合成具有同等的抑制作用。9cRA和全反式视黄酸都能诱导SK-BR-3细胞系中黏附分子E-钙黏蛋白的表达。我们建议应考虑对9cRA和TAM联合使用进行临床评估，用于化学预防或辅助治疗。
