Naturally occurring molecules with putative
cancer chemopreventive properties such as the phytoalexin
resveratrol (3,5,4'-trihydroxystilbene) are lead molecules that guide the design of novel agents with improved pharmacologic properties. The synthetic
resveratrol analog
3,4,5,4'-tetramethoxystilbene (DMU-212) has been shown to possess stronger antiproliferative properties in human
colon cancer cells than
resveratrol. We tested the hypothesis that
DMU-212 is also a more potent inhibitor of
adenoma development in the Apc(Min+) mouse, a model of human intestinal
carcinogenesis. Apc(Min+) mice received either
stilbene derivative with the diet (0.2%), and
adenomas were counted after experiments were terminated.
Resveratrol and
DMU-212 decreased
adenoma load by 27% and 24%, respectively, compared to untreated controls.
Cyclooxygenase (COX)
enzymes are important mechanistic targets of
resveratrol, and we investigated whether
DMU-212 interferes with the expression and activity of COX in human colon cells. Incubation of HCA-7
cancer cells for 24-96 hr with either
stilbene derivative (1-50 microM) decreased
prostaglandin E-2 (PGE-2) production, but only
resveratrol decreased COX-2
protein expression. In mice, which received either
stilbene derivative (0.2%) for 3 weeks with their diet, PGE-2 levels in the intestinal mucosa were reduced by between 45% and 62% compared to mice on control diet. While
resveratrol inhibited
enzyme activity in purified COX preparations,
DMU-212 failed to do so. The PGE-2 decrease seen with
DMU-212 in cells and in vivo is probably mediated via its metabolites. The results suggest that alteration of the
resveratrol molecule to generate
DMU-212 does not abrogate its ability to decrease
adenoma number in Apc(Min+) mice or to interfere with PGE-2 generation in cells.