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.
|Boutros, Cherif; Somasundar, Ponnandai; Razzak, Anthony et al. (2010) Omega-3 fatty acids: investigations from cytokine regulation to pancreatic cancer gene suppression. Arch Surg 145:515-20|
|Aldridge, Christopher; Razzak, Anthony; Babcock, Tricia A et al. (2008) Lipopolysaccharide-stimulated RAW 264.7 macrophage inducible nitric oxide synthase and nitric oxide production is decreased by an omega-3 fatty acid lipid emulsion. J Surg Res 149:296-302|
|Razzak, Anthony; Aldrich, Chris; Babcock, Tricia A et al. (2008) Attenuation of iNOS in an LPS-stimulated macrophage model by omega-3 fatty acids is independent of COX-2 derived PGE2. J Surg Res 145:244-50|
|Dekoj, Thomas; Lee, Sang; Desai, Sagun et al. (2007) G2/M cell-cycle arrest and apoptosis by n-3 fatty acids in a pancreatic cancer model. J Surg Res 139:106-12|
|Sharif, Suhail; Broman, Michael; Babcock, Tricia et al. (2006) A priori dietary omega-3 lipid supplementation results in local pancreatic macrophage and pulmonary inflammatory response attenuation in a model of experimental acute edematous pancreatitis (AEP). JPEN J Parenter Enteral Nutr 30:271-6|
|Babcock, Tricia A; Dekoj, Thomas; Espat, N Joseph (2005) Experimental studies defining omega-3 fatty acid antiinflammatory mechanisms and abrogation of tumor-related syndromes. Nutr Clin Pract 20:62-74|
|Zgodzinski, Witold; Dekoj, Thomas; Espat, N Joseph (2005) Understanding clinical issues in postoperative nutrition after pancreaticoduodenectomy. Nutr Clin Pract 20:654-61|
|Jho, David H; Cole, Shawn M; Lee, Ellyn M et al. (2004) Role of omega-3 fatty acid supplementation in inflammation and malignancy. Integr Cancer Ther 3:98-111|
|Babcock, Tricia A; Helton, W Scott; Anwar, Khandaker N et al. (2004) Synergistic anti-inflammatory activity of omega-3 lipid and rofecoxib pretreatment on macrophage proinflammatory cytokine production occurs via divergent NF-kappaB activation. JPEN J Parenter Enteral Nutr 28:232-9; discussion 239-40|
|Breen, Heather B; Espat, N Joseph (2004) The ubiquitin-proteasome proteolysis pathway: potential target for disease intervention. JPEN J Parenter Enteral Nutr 28:272-7|
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