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Biomed Pharmacother. 2016 Mar;78:291-300. doi: 10.1016/j.biopha.2016.01.017. Epub 2016 Feb 4.

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

Author information

1
Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350002, China; Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian 350108, China.
2
Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350002, China; School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350108, China.
3
Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350002, China.
4
Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350002, China; Rutgers, The State University of New Jersey,160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
5
Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350002, China. Electronic address: cmapcjia1234@163.com.

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.

KEYWORDS:

Cancer metastasis chemoprevention; Cytostatic; Integrin α4; Metapristone; Mifepristone

PMID:
26898454
DOI:
10.1016/j.biopha.2016.01.017
[Indexed for MEDLINE]

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