J Van heusden 1 , R Van Ginckel 1 , H Bruwiere 1 , P Moelans 1 , B Janssen 1 , W Floren 1 , B J van der Leede 1 , J van Dun 1 , G Sanz 3 , M Venet 3 , L Dillen 2 , C Van Hove 2 , G Willemsens 2 , M Janicot 1 , W Wouters 4
12 February 2002
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 n M. 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