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5,6-Epoxyretinoic acid opposes the effects of 12-O-tetradecanoylphorbol-13-acetate in bovine lymphocytes

Naturevolume 277pages227229 (1979) | Download Citation



12-O-TETRADECANOYLPHORBOL-13-ACETATE (TPA), the most potent of a series of tumour-promoting agents isolated from croton oil1, has been found to be highly active in bovine lymphocytes as a stimulator of choline phospholipid metabolism2, an inducer of ornithine decarboxylase3, and a co-mitogen when used in conjunction with phytohaemagglutinin (PHA)4,5. These effects of TPA in the bovine lymphocyte system are antagonised by retinoic acid2,5, an agent which opposes the tumour-promoting action of phorbol esters in mouse skin6,7 and inhibits chemical carcinogenesis in several other tissues8. However, the dose–response curves for retinoic acid in inhibiting these effects in lymphocytes are broad and extend over several orders of magnitude, suggesting that retinoic acid may have to be metabolised to be biologically effective in this system. The possibility that epoxidation might be involved in the activation of retinoic acid and related retinoids was suggested by two observations. First, 10, 11-epoxymethylfarnesoate (insect juvenile hormone III), which bears the epoxide moiety at a position corresponding to the double bond in the ionone ring of retinoic acid, was found to oppose the actions of TPA in bovine lymphocytes and exhibited a much steeper dose–response curve9. Second, we have demonstrated that epoxidation at the 5,6-position of β-ionone strikingly increases its activity as an antagonist of the co-mitogenic action of TPA as well as the TPA stimulation of phospholipid metabolism10. We describe here the chemical synthesis and biological testing of the 5,6-epoxy derivative of retinoic acid as an antagonist of TPA action in bovine lymphocytes. We report that the introduction of an epoxide group at this position results in an enhanced ability to oppose certain effects of TPA in these cells.

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  1. McArdle Laboratory for Cancer Research, The University of Wisconsin, Madison, Wisconsin, 53706

    • , AJIT K. VERMA
    •  & R. K. BOUTWELL


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