Study Of The Compare Metapristone To Mifepristone In Toxicology And Pharmacology By Establishment Animal Tumor Metastasis Models

Objective:Metapristone is the most predominant biological active metabolite of mifepristone(RU486),and being developed as a novel cancer metastatic chemopreventive based on its unique pharmacological properties.The aim of the present study was to evaluate the toxicity,and effect in isolated rat organs of metapristone and its parent drug mifepristone.To investigate the cancer metastasis prevention effect of metapristone and mifepristone.We completed the pre-clinical research of metapristone and lay the foundation for later research and drug discovery.Methods:The purpose of this work was to investigate its smooth muscle contraction effect in isolated rat organs such as small intestine,stomach and thoracic aorta.Healthy KM mice of both sexes were used in acute toxicity assay.Metapristone administrated by gavage with single doses of 500,1000,2000,3000 mg/kg,respectively.Mifepristone was used only the highest dose relative to metapristone,namely 3000 mg/kg.The general behaviour of the mice were observed after dosing over the next 14 days.The duration of subacute toxicity studies involved oral administration of mifepristone(200 mg/kg/day)or metapristone(12.5,50 or 200 mg/kg/day)to SD rats.All rats were observed daily for pharmacotoxic and body weights were measured periodically.The food intake and water consumed was also measured daily.At the end of the 30 days-experiment,rats were anaesthetized using anesthetic ether and blood samples collected via cardiac puncture for blood chemistry and hematologic analyses.The following organs were observed lesions.The recovery of organs were observed in rats after withdrawal.To establish animal tumor metastasis model with B16-F10 murine melanoma cells,LLC Lewis lung cancer cells and 4T1 breast cancer cells.Mice were treated with mifepristone or metapristone,respectively.At the end of experinents,mice were sacrificed and lung tumor nodules and lung weight were recorded.The aim of these studies were to evaluate the cancer metastasis prevention of metapristone and its parent drug mifepristone.Results:Metapristone induced smooth muscle contraction of small intestine,stomach and thoracic aorta in a dose-dependent manner.The LD50 value of mifepristone or metapristone in KM mice of acute toxicity study was higher than 3000 mg/kg.The liver in the dose of 50,200 mg/kg/d metapristone or 200 mg/kg/d mifepristone groups showed vacuoles of various sizes appeared in the swelling of liver cells and nuclei with normal morphology.The vacuoles were the fatty degeneration in liver cells.The other organ pathological changes were not found.The liver toxicity of metapristone was slighter than mifepristone,and influence female rats were more serious than male.These effects on the liver would gradually disappear with the longer duration of drug withdrawal.Mifepristone and metapristone suppressed B16-F10 murine melanoma cells,LLC Lewis lung cancer cells or 4T1 breast cancer cells metastasis to mice lungs.The effect of cancer metastasis prevention of metapristone was better than mifepristone.And this effect of metaprimtone present a dose-dependent.Conclusion:The results in the present study revealed that the most severe pathological changes were on the liver,and no toxicity of other organs.And we observed less toxic reaction of metapristone than mifepristone in SD rats.Metapristone had a remarkable effect of preventing cancer metastasis on animal tumor metastasis models compared with mifepristone.Metapristone may fit into a more safe and effective drug for cancer prevention or treatment than mifepristone.