PRECLINICAL EVALUATIONS OF INTERMEDIATE ENDPOINTS

本项目的目标是确定其作用机制。 4HPR、维甲酸乙酯和9顺式维甲酸。N-甲基-N-亚硝脲 (MNU)正被用于在Spraogue-Dawley大鼠身上产生乳腺肿瘤。这个 动物正在接触三种维甲酸(9-顺式维甲酸，4 HPR和视黄酸乙酯)，为期六周。单个肝脏、乳房 腺体和肺的编码RNA的表达 RARα、RARβ、RXRα和另一个受 维甲酸。MNU单独治疗或MNU治疗大鼠的乳腺肿瘤 MNU加维甲酸用于确定长期疗效 肿瘤组织上的维甲酸。这些组织中的细胞凋亡水平是 使用已公布的标准测量技术进行测量 细胞凋亡。中国人乳腺肿瘤发生的基因改变 啮齿动物和人类正在接受检查。肝脏样本也在被 研究以确定大鼠基因组显示上的潜在标记 要检查的特定位点的杂合性。乳腺肿瘤和 更有限数量的乳房组织“正常”区域正在被 检测与人类7Q同线的区域的杂合性丢失 这些动物肿瘤中的区域。DMBA诱导的F1小鼠肿瘤也 正在检查是否丢失了与人类7Q区共线的区域。

The objective of this project is to determine the mechanism of action of 4HPR, retinyl acetate and 9 cis retinoic acid. N-methyl-N-nitrosourea (MNU) is being used to generate mammary tumors in Sprague-Dawley rats. The animals are being exposed to the three retinoids (9-cis retinoic acid, 4 HPR, and retinyl acetate) for six weeks. Individual livers, mammary glands, and lungs are examined for the expression of the RNAs coding for RAR alpha, RAR beta , RXR alpha and one other gene which is modulated by retinoids. Mammary tumors from rats treated with MNU-alone or rats treated with MNU plus retinoid are used to determine the long term effects of the retinoids on tumor tissues. The levels of apoptosis in these tissues are being measured employing standard published techniques for measuring apoptosis. The genetic changes associated with mammary tumorigenesis in rodents and humans are being examined. Liver samples are also being studied to determine whether potential markers on the rat genome display heterozygosity at the specific sites to be examined. Mammary tumors and a more limited number of "normal" regions of breast tissue are being examined for loss of heterozygosity in regions syntenic to the human 7Q region in these animal tumors. DMBA -induced tumors from Fl mice are also being examined for the loss of the region syntenic to the human 7Q region.