Avis I, Mathias A, Unsworth E J, Miller M J, Cuttitta F, Mulshine J L, Jakowlew S B
National Cancer Institute, Biomarkers and Prevention Research Branch, Rockville, Maryland 20850-3300, USA.
Cell Growth Differ. 1995 May;6(5):485-92.
13-cis-Retinoic acid can mediate differentiation of transformed cells and slow the proliferation of malignant cells, suggesting its use as a potential intervention tool. Specific cDNA probes for retinoic acid receptors demonstrated the expression of mRNAs for the different retinoic acid receptor isoforms in small cell lung cancer cell lines. Addition of 13-cis-retinoic acid to small cell lung cancer cells cultured using serum-free, hormonally defined medium resulted in a 5-8-fold increase in the level of the retinoic acid receptor-beta mRNAs; in medium containing serum, the increase in expression of the retinoic acid receptor-beta mRNAs was less pronounced, usually no more than 2-fold. Using an in vitro proliferation assay, addition of 13-cis-retinoic acid resulted in a significant dose-dependent, growth-inhibitory effect on the small cell lung cancer cell lines tested using serum-free conditions. These inhibitory effects decreased when cells were cultured in medium containing serum or serum components. Molecular size exclusion chromatography and native gel electrophoresis showed that the causative serum component eluted and migrated with serum albumin. Preincubating serum with triglycerides restored the inhibitory effects of 13-cis-retinoic acid demonstrated in serum-free systems. These data suggest that 13-cis-retinoic acid preferentially binds to serum albumin, restricting its inhibitory effects on epithelial cell receptors. Blocking retinoic acid-albumin interactions with a fatty acid source may improve the bioavailability of 13-cis-retinoic acid and significantly enhance the inhibitory effect in vivo.
13 - 顺式维甲酸可介导转化细胞的分化并减缓恶性细胞的增殖，这表明其可作为一种潜在的干预工具。针对维甲酸受体的特异性cDNA探针显示，在小细胞肺癌细胞系中存在不同维甲酸受体亚型的mRNA表达。在使用无血清、激素限定培养基培养的小细胞肺癌细胞中添加13 - 顺式维甲酸，可使维甲酸受体 - β mRNA水平增加5 - 8倍；在含有血清的培养基中，维甲酸受体 - β mRNA表达的增加则不太明显，通常不超过2倍。使用体外增殖试验，在无血清条件下添加13 - 顺式维甲酸对所测试的小细胞肺癌细胞系产生了显著的剂量依赖性生长抑制作用。当细胞在含有血清或血清成分的培养基中培养时，这些抑制作用会减弱。分子排阻色谱和天然凝胶电泳显示，起作用的血清成分与血清白蛋白一起洗脱和迁移。用甘油三酯对血清进行预孵育可恢复在无血清系统中所显示的13 - 顺式维甲酸的抑制作用。这些数据表明，13 - 顺式维甲酸优先与血清白蛋白结合，限制了其对上皮细胞受体的抑制作用。用脂肪酸源阻断维甲酸 - 白蛋白相互作用可能会提高13 - 顺式维甲酸的生物利用度，并显著增强其体内抑制作用。
