Growth-inhibitory Mechanisms of Synthetic Retinoids on Human Gastric Cancer Cells

• Main Author: 林鼎晏
• Other Authors: 葉明陽
• Format: Others
• Language: zh-TW
• Published: 1997
• Online Access: http://ndltd.ncl.edu.tw/handle/89833583397430488780

碩士 === 國防醫學院 === 微生物及免疫學研究所 === 85 === Gastric cancer is the third most common cause of cancer death in Taiwan. It is important to search for new treatment modalities. In the past decades, retinoic acid (RA) has been recognised as an important compound in cell differentiation, proliferation and malignant transformation. The action of RA on gene regulation is mediated by two classes of nuclear receptors, the retinoic acid receptor (RARs) and the retinoid X receptors (RXRs). Although RA displays a wide spectrum of antitumour activities, side effects are drawbacks of the compound. In order to find a more specific drug with high therapeutic index and low teratogenic risk, a number of receptor selective compounds have been recetly identified. In this thesis, I have studied effects and mechanisms of tRA and three synthetic retinoids, which exhibiting high selectivity for RARα (Am 580). RARβ (CD 2019)and RARγ (CD 437) on the growth of gastric cancer cells. tRA inhibited the growth of three(SC-M1, TSGH9201 and AGS)out of five gastric cancer cells. CD 437 had much more profound growth suppression activity than that of tRA and displayed a wide range of growth inhibitory effects on cancer cells. However, the primary aminotic cells were less sensitivity to CD 437. No correlation was found between mRNA levels of RARγ and CD 437 sensitivity. Furthermore, growth inhibition induced by CD 437 was not reversed by tRA, which binds RARγ with high affenity.These results indicated that CD 437 inhibited the growth of cancer cells via RARγ-independent pathway. Am 580 and CD 2019 exhibited little or no activity on gastric cancer cells. The growth inhibition induced by CD 437 was associated with the apoptotic process. Besides, CD 437 slightly suppressed levels of bcl-2 protein. The increase in expression of p21 protein levels and much lower basal levels of CDK2 and CDK4 in AGS cells may be the result that CD 437 induced G0/G1 arrest. High basal levels of CDK2 and CDK4 proteins and decrease in levels of p21 protein may not perturb G1-S transition in SC-M1 cells treated with CD 437. Instead, CD 437 may activate or inactivate some factors that prevent the activation of cyclin B/ p34cdc2 and then lead to the G2 phase arrest. In summary, CD 437 represents a novel retinoid that induces growth inhibition, through either G0/G1 or G2/M arrest in gastric cancer cells. The growth suppression is mediated through pathways of apoptosis. The genuine mechanisms by which CD 437-induced apoptosis and G2/M arrest is unknow and worth to be studied further.