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Title: Comparative pre-clinical evaluation of resveratrol and 3,4,5,4'-tetramethoxystilbene (DMU212) as colorectal cancer chemopreventive agents
Author: Sale, Stewart
ISNI:       0000 0001 2437 5972
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2005
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Recently a variety of analogues of resveratrol have been synthesised and investigated in in vivo assays. One analogue, 3,4,5,4'-tetramethoxystilbene (DMU212), showed preferential growth-inhibitory and pro-apoptotic properties in transformed cells, when compared with their untransformed counterparts. Cyclooxygenase enzymes are important mechanistic targets of resveratrol. As part of this study the pharmacokinetic properties of DMU212 were compared with those of resveratrol. Both agents were also compared in terms of abilities to prevent adenoma development in the ApcMin+ mouse, a model of human intestinal carcinogenesis, and to interfere with the expression and activity of COX in human-derived colon cells. Pharmakinetic data showed that resveratrol achieved significantly higher levels than DMU212 systematically, whilst DMU212 exhibited superior availability in the gastrointestinal tract. ApcMin+ mice received either compound with the diet (0.05, 0.2 or 0.5 %), and adenomas were counted after animals were killed. Resveratrol and DMU212 at 0.2 % decreased adenoma load by 27 and 24 % respectively. DMU212 is a better inhibitor of proliferation of human colon cancer cells than resveratrol. Incubation of HCA-7 colon cancer cells for 24-96 h with either compound (1-50 microM) decreased PGE2 production, but only resveratrol decreased COX-2 protein expression. Whilst resveratrol inhibited enzyme activity in purified COX preparations, DMU 212 failed to do so. The results suggest that chemical alteration of the resveratrol molecule to generate DMU212 does not alter its ability to decrease adenoma number in ApcMin+ mice or to interfere with PGE2 generation in cells. However, only resveratrol directly inhibits COX activity and expression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available