Date of Award

1-1-2011

Document Type

Campus Access Dissertation

Department

Exercise Science

First Advisor

J. Mark Davis

Abstract

Effects of 5-Fluorouracil Chemotherapy on Fatigue and Inflammation in Mice: Benefits of Quercetin Cancer related fatigue is one of the most distressing symptoms reported by cancer patients, however little research has been done to elucidate the cause(s) of this debilitating condition. Because nearly all cancer patients undergo harsh chemotherapy treatments, it is unclear whether the fatigue they suffer is caused by the cancer, the chemotherapy, or their combination. Additionally, chemotherapy treatments have been shown to induce an increase in inflammation, which may be contributing to fatigue. The purpose of this study was to determine the effect of chemotherapy alone on 24 hr voluntary wheel running activity in healthy mice, as well as to determine the potential role of inflammatory cytokines and the potential benefits of quercetin supplementation. C57BL/6 mice were assigned to one of four treatments: placebo (PBS), low (20 mg/kg), standard (40mg/kg), or high (60 mg/kg) doses of 5-fluorouracil, a common chemotherapy used for colorectal cancer (n = 12/group). Physical activity was measured throughout the treatment period (day 1-5) as well as during the recovery period (day 6-14) using cages equipped with running wheels that allow for continuous monitoring of running time, peak speed and total distance. A dose-response effect was found in distance, time and speed run following administration of 5-FU. The effect of quercetin on voluntary wheel cage running was assessed using C57BL/6 mice assigned to one of four groups; normal diet-placebo (ND-PLA), normal diet-5-FU (ND-60), quercetin-placebo (Q-PLA), and quercetin-5-FU (Q-60). Voluntary wheel running was significantly reduced in both the ND-60 and Q-60 groups following 5-FU injection (p < 0.05), however, the Q-60 group was not significantly different from Q-PLA by day 7, whereas the ND-60 group remained significantly lower than ND-PLA(p <0.05) for the duration of the experiment. In Experiment 1, red blood cell, hemoglobin, and hematocrit concentrations were significantly reduced in the 40 mg/kg and 60 mg/kg groups as compared to placebo, both at 12 hours post and 10 days post (p<0.05). In the 40 mg/kg dose, IL-6 and MCP-1 were slightly elevated in the cortex at 5 and 14 days, respectively, but were not elevated in the 60 mg/kg dose. However, MCP-1 was significantly elevated in the plasma in the 60 mg/kg dose. To confirm to role of MCP-1, the voluntary activity experiment was repeated using MCP-1 -/- mice. While both C57BL/6 and MCP-1-/- mice saw similar decrements in voluntary activity through the duration of the treatment, the knockout mice recovered to baseline levels of activity by day 9, whereas the B6 mice did not recover through 14 day. In Experiment 2, both the ND and Q groups had reduced red blood cells, hematocrit and hemoglobin at 5 days, but the quercetin group was significantly higher than the normal diet group in all three measures at 14 days (p < 0.001). MCP-1 was significantly elevated in the plasma at 14 days in the normal diet group, but no changes were seen in the quercetin group as compared to placebo. This demonstrates the beneficial role of quercetin not only in reducing MCP-1, but in blunting the severity of common side effects such as fatigue and anemia following chemotherapy treatment. This study is evidence that quercetin may be a feasible and effective treatment for chemotherapy-induced fatigue and its use with chemotherapy treatment may allow greater and more effective doses to be used.

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