1. Inhibition of all-TRANS-retinoic acid metabolism by R116010 induces antitumour activity.
- Author
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Van Heusden J, Van Ginckel R, Bruwiere H, Moelans P, Janssen B, Floren W, van der Leede BJ, van Dun J, Sanz G, Venet M, Dillen L, Van Hove C, Willemsens G, Janicot M, and Wouters W
- Subjects
- Animals, Benzothiazoles, Breast Neoplasms metabolism, Breast Neoplasms pathology, Breast Neoplasms prevention & control, Cell Division drug effects, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 Enzyme System metabolism, Dose-Response Relationship, Drug, Female, Humans, Mammary Neoplasms, Experimental metabolism, Mice, Mice, Inbred Strains, Mixed Function Oxygenases genetics, Mixed Function Oxygenases metabolism, Retinoic Acid 4-Hydroxylase, Reverse Transcriptase Polymerase Chain Reaction, Tretinoin pharmacology, Tumor Cells, Cultured drug effects, Antineoplastic Agents pharmacology, Cytochrome P-450 Enzyme Inhibitors, Imidazoles pharmacology, Mammary Neoplasms, Experimental prevention & control, Mixed Function Oxygenases antagonists & inhibitors, Thiazoles pharmacology, Tretinoin metabolism
- Abstract
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 IC(50)-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.
- Published
- 2002
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