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

Abstract

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.

• Authors: Jichuang Wang, Jianzhong Chen, Yewei Zhu, Ning Zheng, Jian Liu, Yingying Xiao, Yusheng Lu, Haiyan Dong, Jingjing Xie, Suhong Yu, Jingwei Shao, Lee Jia
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 78 Pg. 291-300 (Mar 2016) ISSN: 1950-6007 [Electronic] France
• PMID: 26898454 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Chemical References

• Anticarcinogenic Agents
• Integrin alpha4
• Mifepristone
• metapristone

Topics

• Animals
• Anticarcinogenic Agents (adverse effects, therapeutic use)
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chemoprevention
• Disease Models, Animal
• Female
• Integrin alpha4 (metabolism)
• Liver (drug effects, pathology)
• Lung Neoplasms (drug therapy, pathology, prevention & control, secondary)
• Melanoma, Experimental (pathology)
• Mice, Inbred C57BL
• Mifepristone (adverse effects, analogs & derivatives, therapeutic use, toxicity)
• Treatment Outcome