Development of a Biologically-based Nursing Intervention for Cancer Cachexia

Ohio State University, Columbus OH

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Abstract

DESCRIPTION (provided by applicant): Cachexia is a syndrome of anorexia, weight loss and skeletal muscle wasting. The loss of muscle mass contributes to symptoms of fatigue and weakness reported by 80% of persons with cancer, and negatively impacts functional status and quality of life of patients with cancer cachexia. The long range goal of this program of research is the development and testing of biologically-based nursing interventions to preserve muscle mass in patients with cancer cachexia. Muscle mass is a dynamic balance between myofibril synthesis and degradation. Cachexia is associated with decreased expression of insulin-like growth factor-1 (IGF-1), a requisite mediator of myofibril synthesis, and increased expression and activity of the ubiquitin-proteasome pathway (UPP) of myofiber degradation, mediated in great part by the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFa). Many of the effects of TNFa are mediated by cyclo-oxygenase2 (COX2), the rate limiting enzyme in the synthesis of pro-inflammatory prostanoids. The principal investigator (PI) has demonstrated that treatment of tumor-bearing mice with nonsteroidal anti-inflammatory drugs (NSAIDs) that block COX2 activity preserved gastrocnemious (gastroc) muscle mass and reduced muscle expression of TNFa type 1 receptors (TNFR1) in one model of cancer cachexia, but not in another. Because these experiments were conducted in the same strain of mice, these data suggest that tumor-induced skeletal muscle wasting can occur by both COX2-dependent and independent pathways. The purpose of the proposed descriptive comparative study is to compare the effects of these two tumor models on muscle expression of selected biomarkers of protein synthesis and/or myofiber degradation, and to determine which of these biomarkers are affected by treatment with NSAIDs. The study will be conducted using frozen gastroc muscle samples from over 250 mice prepared in prior studies in the Principal Investigator's laboratory. Undergraduate and graduate nursing students will be trained in laboratory methods of western blotting, enzyme-linked immunoassays, and real-time PCR for measurement of selected biomarkers of muscle protein metabolism. The findings from this study will increase our understanding of the pathobiology of tumor-induced muscle wasting and inform future studies to determine if NSAIDS might be beneficial in the treatment of cancer cachexia. The involvement of undergraduate students in nursing research should increase the number of students pursuing doctoral studies in the College of Nursing. Symptom management of illness and treatment is an important component of quality of life and a major focus of the NINR mission. This program of research will contribute to the development and testing of biologically-based nursing interventions to preserve muscle mass and reduce symptoms of fatigue and weakness in patients with cancer cachexia. PUBLIC HEALTH RELEVANCE: A syndrome of anorexia, weight loss, muscle wasting, weakness, and fatigue called cancer cachexia causes significant morbidity and mortality among patients with advanced cancer. This syndrome is caused in great part by proinflammatory mediators that decrease protein synthesis and increase muscle protein degradation. There is some evidence that anti-inflammatory drugs preserve muscle mass in tumor-bearing mice, though the mechanism of action is not known. This information is needed to determine if these drugs might be useful in the treatment of cancer cachexia. The proposed study will examine the effects of these drugs on biomarkers of muscle metabolism using muscle samples from prior studies in the principal investigator's laboratory. Undergraduate nursing students will participate in the study, which should increase their interest in nursing research and pursuit of a Doctoral degree in Nursing. The findings from this study will lead to the development and testing of biologically-based nursing interventions to alleviate cachexia in cancer patients.