Inhibition of all-TRANS-retinoic acid metabolism by R116010 induces antitumour activity
| Autor: | Gerard Charles Sanz, B Janssen, J. Van Dun, L Dillen, C. Van Hove, Walter Wouters, J Van heusden, P Moelans, H Bruwiere, R Van Ginckel, G Willemsens, B.-J. Van Der Leede, Wim Floren, Michel Janicot, Marc Venet |
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| Jazyk: | angličtina |
| Rok vydání: | 2002 |
| Předmět: |
Cancer Research
Retinoic acid Antineoplastic Agents Breast Neoplasms Mice Inbred Strains Tretinoin Biology Pharmacology Mixed Function Oxygenases chemistry.chemical_compound Mice Cytochrome P-450 Enzyme System In vivo medicine Tumor Cells Cultured R116010 Animals Cytochrome P-450 Enzyme Inhibitors Humans Liarozole Experimental Therapeutics Benzothiazoles Chromatography High Pressure Liquid Dose-Response Relationship Drug Cell growth Reverse Transcriptase Polymerase Chain Reaction Imidazoles Mammary Neoplasms Experimental Biological activity Metabolism Retinoic Acid 4-Hydroxylase inhibitor Thiazoles Oncology chemistry Mechanism of action Biochemistry CYP26A1 Female medicine.symptom RA metabolism Cell Division medicine.drug |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | All-trans-retinoic acid is a potent inhibitor of cell proliferation and inducer of differentiation. However, the clinical use of all-trans-retinoic acid in the treatment of cancer is significantly hampered by its toxicity and the prompt emergence of resistance, believed to be caused by increased all-trans-retinoic acid metabolism. Inhibitors of all-trans-retinoic acid metabolism may therefore prove valuable in the treatment of cancer. In this study, we characterize R116010 as a new anticancer drug that is a potent inhibitor of all-trans-retinoic acid metabolism. In vitro, R116010 potently inhibits all-trans-retinoic acid metabolism in intact T47D cells with an IC50-value of 8.7 nM. In addition, R116010 is a selective inhibitor as indicated by its inhibition profile for several other cytochrome P450-mediated reactions. In T47D cell proliferation assays, R116010 by itself has no effect on cell proliferation. However, in combination with all-trans-retinoic acid, R116010 enhances the all-trans-retinoic acid-mediated antiproliferative activity in a concentration-dependent manner. In vivo, the growth of murine oestrogen-independent TA3-Ha mammary tumours is significantly inhibited by R116010 at doses as low as 0.16 mg kg−1. In conclusion, R116010 is a highly potent and selective inhibitor of all-trans-retinoic acid metabolism, which is able to enhance the biological activity of all-trans-retinoic acid, thereby exhibiting antitumour activity. R116010 represents a novel and promising anticancer drug with an unique mechanism of action. British Journal of Cancer (2002) 86, 605–611. DOI: 10.1038/sj/bjc/6600056 www.bjcancer.com © 2002 Cancer Research UK |
| Databáze: | OpenAIRE |
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