The primary purpose of this mentored award is to prepare the applicant for a career as an independent physician scientist. The applicant proposes to acquire additional skills in cell biology and molecular analysis in the context of a project that is directly relevant to his clinical specialty. The-long term goals are: 1) to investigate the mechanism(s) and define the relationship between tumor related inflammation and cancer associated cachexia; and 2) to develop safe and effective anti-inflammatory treatment strategies for patients with progressive malignancy using (nutritional) eicosapentaenoic acid, (EPA)) and/or (pharmacologic) selective cyclo-oxygenase-II (COX-II) inhibitor agents. Anorexia, weight loss and the catabolism of lean body mass define the clinical syndrome of cancer-associated cachexia. Preventing or delaying cachexia is a clinically significant goal, since improved outcome and survival for cancer patients has been consistently demonstrated to parallel the preservation of lean body mass. 1-4 Clinical and experimental evidence from our lab and others supports the use of EPA as an anti-inflammatory therapy. EPA is a w-3 fatty acid that may attenuate the production of pro-inflammatory cytokines, growth factors and inflammatory mediators, in response to inflammatory stimuli, however the mechanism(s) remain to be defined. Hypothesis: EPA alone or in combination with COX-II inhibitors attenuate the tumor-related inflammation of progressive malignancy. To test this hypothesis we will use the in vitro RAW 264-7 cell culture model and the well-established rodent model of progressive malignancy resulting in cancer-cachexia, the methyl-cholanthrene (MCA) fibrosarcoma, with the following specific aims.
AIM1 : To evaluate in vitro EPA and/or COX-II inhibition of macrophage TNF-alpha, IL-1beta, prostaglandin E2, COX-II enzyme production, NF-kB activity and apoptosis.
AIM 2 : To evaluate in vivo EPA and/or COX-II inhibition therapies of tumor-related TNF-alpha, IL-1beta, prostaglandin E2, COX-Il enzyme production, NF-kB activity, apoptosis and regulation of the ubiquitin proteasome proteolytic pathway in response to progressive non-metastasizing malignancy.
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