Comparison of octahydromezerein and mezerein as protein kinase C activators and as mouse skin tumor promoters.
Comparison of octahydromezerein and mezerein as protein kinase C activators and as mouse skin tumor promoters.
复制标题
八氢 mezerein 和 mezerein 作为蛋白激酶 C 激活剂和小鼠皮肤肿瘤促进剂的比较。
作者：
N. A. Sharkey;H. Hennings;S. Yuspa;P. Blumberg
虽然美泽瑞因在体外作为蛋白激酶C的有效配体方面类似于12-O-十四酰基佛波醇-13-乙酸酯（TPA），但其作为小鼠皮肤上的肿瘤促进剂的性质不同于TPA。Mezerein是一个很好的乳头状瘤的第二阶段启动子，一个低效的乳头状瘤的完全启动子，和一个有效的癌的启动子。美泽瑞因异常促肿瘤活性的机制和结构特征尚不清楚。我们在这里检查了八氢美泽瑞因（OHM）的体外和体内活性，并将其与TPA和美泽瑞因的活性进行了比较。OHM是感兴趣的，因为如果它像美泽瑞因一样起作用，它将为放射性标记提供方便的途径。或者，如果它作为一个完整的肿瘤促进剂，它将牵连不饱和度的关键结构特征的美泽瑞因负责其改变的促进活性。与后一种可能性一致，我们发现OHM是SENCAR小鼠有效的完全肿瘤促进剂。此外，乳头状瘤诱导的模式和幅度，在16-20周达到峰值，随后在30-32周下降，与TPA相似;相反，美泽瑞因诱导乳头状瘤数量逐渐但稳定增加，到32周未达到OHM水平。与美泽瑞因相比，诱导急性和慢性增生程度相当的OHM剂量高3至10倍。这种差异与蛋白激酶C的相对结合亲和力一致; OHM的Ki为2.7 nM，而美泽瑞因为0.58 nM。
Although mezerein resembles 12-O-tetradecanoylphorbol-13-acetate (TPA) in being a potent ligand for protein kinase C in vitro, its properties as a tumor promoter on mouse skin differ from those of TPA. Mezerein is a good second-stage promoter of papillomas, an inefficient complete promoter of papillomas, and an effective promoter of carcinomas. The mechanism and structural features responsible for the anomalous tumor promoting activity of mezerein are unknown. We have examined here the in vitro and in vivo activities of octahydromezerein (OHM) and compared them to those of TPA and mezerein. OHM was of interest because if it acted like mezerein it would afford a convenient route for radioactive labeling. Alternatively, if it functioned as a complete tumor promoter, it would implicate unsaturation as the critical structural feature of mezerein responsible for its altered promoting activity. Consistent with this latter possibility, we find that OHM was an effective complete tumor promoter for SENCAR mice. Moreover, the pattern and magnitude of papilloma induction, yielding a peak at 16-20 weeks followed by a decline by 30-32 weeks, resembled that for TPA; mezerein, in contrast, induced a gradual but steady increase in the number of papillomas which did not reach the OHM level by 32 weeks. The dosage of OHM for inducing a comparable degree of acute and chronic hyperplasia to that induced by mezerein was 3- to 10-fold higher. This difference agrees with the relative binding affinities to protein kinase C; the Ki for OHM was 2.7 nM, compared to 0.58 nM for mezerein.