Novel coumarins as potential anticarcinogenic agents.
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abstract
The potential anticarcinogenic properties of several novel coumarin derivatives whose structures are based on polycyclic aromatic hydrocarbons (PAHs) were examined in the multistage model of mouse skin tumorigenesis. The test compounds were evaluated for their affinity to bind competitively with rat cytosolic Ah-receptor in rat hepatic cytosol, their effects on mouse epidermal aryl hydrocarbon hydroxylase (AHH) after topical application, and for their effects on the levels of hydrocarbon-DNA adducts formed in vivo. All compounds showed good correlations between cytosolic Ah-receptor binding and their ability to induce epidermal AHH activity. Among the derivatives evaluated the coumarin (8-methyl-9H-10-oxabenzo[a]pyren-9-one) exhibited the highest affinity for the Ah-receptor and was also the most potent inducer of epidermal AHH activity. This compound also effectively inhibited the covalent binding of 7,12-dimethylbenz[a]anthracene (DMBA) to epidermal DNA when given either 5 min or 24 h prior to application of [3H]DMBA. This novel coumarin derivative significantly inhibited skin tumor initiation by DMBA in SENCAR mice when given at a dose of 200 nmol, 5 min (69% inhibition) or 24 h (76% inhibition) prior to initiation. The results of these studies suggest that this class of compounds shows considerable promise for future development as potential inhibitors of PAH-mediated tumor initiation on mouse skin. Potential mechanism(s) for the anti-initiating action of these compounds are discussed.
