Optimized NSAIDs for Breast Cancer Prevention
Annual rept. 26 Mar 2006-25 Mar 2006
CALIFORNIA UNIV SAN DIEGO LA JOLLA
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Population studies have shown that women who use non-steroidal anti-inflammatory drugs NSAIDs developbreast cancer less frequently. However, these drugs have side effects toward the stomach, liver and kidneys,particularly at the high doses potentially required to prevent breast cancer. Also, how these agents prevent breastcancer is not understood. This project will develop an optimized NSAID for breast cancer prevention that can betaken safely at high doses, and will determine its mechanisms of action. The side effects of NSAlDs are mainly dueto inhibition of cyclo-oxygenase COX enzymes. Based on preliminary experiments, we hypothesize that thepreventative action of NSAlDs in breast cancer is not solely due to COX inhibition, but rather to alterations of otherbiochemical pathways in breast cells that control their proliferation. We have isolated modified NSAIDs that do notinhibit the COX enzyme, but still retain chemopreventative activity. Testing this COX independent NSAlD in arobust model of breast cancer, the MMTV-wnt1 transgenic mouse, has revealed a trend towards tumor preventionand a significant reduction in gene expression of wnt regulated targets. These data have already encouragedearly, biomarker based, clinical trials in women with breast cancer.
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