In vitro and in vivo efficacy and safety evaluation of metapristone and mifepristone as cancer metastatic chemopreventive agents

详细信息    查看全文

• 作者：Jichuang Wang^a ; ^b ; ¹ ; Jianzhong Chen^a ; ^c ; ¹ ; Yewei Zhu^a ; Ning Zheng^a ; Jian Liu^a ; Yingying Xiao^a ; Yusheng Lu^a ; Haiyan Dong^a ; ^d ; Jingjing Xie^a ; Suhong Yu^a ; Jingwei Shao^a ; Lee Jia^a ; ^{cmapcjia1234@163.com" class="auth_mail" title="E-mail the corresponding author} ; ^{pharmlink@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Metapristone ; Mifepristone ; Cytostatic ; Cancer metastasis chemoprevention ; Integrin α4
• 刊名：Biomedicine & Pharmacotherapy
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：78
• 期：Complete
• 页码：291-300
• 全文大小：3553 K

文摘

Malignant melanoma, the most deadly form of skin cancer, has a high propensity for metastatic spread and is notoriously chemotherapy-resistant. Metapristone is the primary metabolite of mifepristone (RU486) and shows biological activities similar to RU486. In the present study, we comprehensively investigated the efficacy of metapristone as a metastatic chemopreventive against melanoma B16F10 cells in vitro and in vivo, and evaluated the safety profile of both drugs in mice. Metapristone showed less cytostatic effect in vitro and in vivo in comparison with mifepristone. However, metapristone interfered the adhesion of B16F10 cells to fibronectin by down-regulating cellular expression of integrin α4. Chemopreventive pretreatment followed by oral administration of metapristone and mifepristone (2.5, 10, 50 mg/kg/day for 35 days) to melanoma C57BL/6 mouse model showed significant attenuation of pulmonary metastatic development. Oral administration of high doses of metapristone and mifepristone to normal mice for 35 days (25, 100, 250 mg/kg/day) resulted in a dose-dependent increase in mouse liver weight that was more severe with mifepristone than metapristone. The long-term toxicity study revealed more changes by mifepristone in counts of erythrocytes, leukocytes and platelets than by metapristone. In conclusion, metapristone may fit into a new class of cancer metastatic chemopreventive agents. It showed a safety and efficacy profile better than mifepristone.