Effects of 5-fluorouracil chemotherapy on fatigue: role of MCP-1

Abstract

Chemotherapy has been known to cause severe side effects, including fatigue. While the mechanisms for chemotherapy induced fatigue (CIF) are likely to be multi-factorial in origin, it is thought that inflammation and anemia may play a role. The purpose of this study was to examine the effect of chemotherapy on fatigue in mice, and further, to begin to determine if inflammation and anemia may contribute to this response. For experiment 1, C57BL/6 mice were assigned to: vehicle (PBS), low (20 mg/kg), medium (40 mg/kg), or high (60 mg/kg) doses of 5-fluorouracil (5-FU). Voluntary physical activity (PA) was measured throughout the treatment period (day 1-5) as well as during the recovery period (day 6-14). In experiment 2, we examined the effects of 5-FU (60 mg/kg) on the inflammatory mediator MCP-1 and on markers of anemia (RBC, Hct and Hb). Finally, using MCP-1(-/-) mice we examined the role of MCP-1 on CIF (experiment 3). 5-FU reduced voluntary PA in a dose response manner (p<0.05). Plasma MCP-1 was increased following 5-FU treatment on both days 5 (p=0.10) and 14 (p<0.05). In addition, RBCs, Hct and Hb were reduced with 5-FU on days 5 and 14 (p<0.05). Both C57BL/6 and MCP-1(-/-) mice saw similar decrements in PA through the duration of the treatment period (days 1-5), however the MCP-1(-/-) mice recovered much earlier than wildtype mice. This study provides evidence of the dose response effect of a standard chemotherapy agent on fatigue and demonstrates a potential role of MCP-1 and presumably inflammation, and anemia.

Fig. 1

Voluntary wheel cage activity for 3 doses of 5-fluorouracil chemotherapy (20, 40 and 60 mg/kg) as compared to vehicle injection (PBS). Data are presented as percent change from baseline (mean ± SE). *p < 0.05 between 40 mg/kg dose and PBS, ^p < 0.05 between 20 mg/kg dose and PBS, #p < 0.05 between 60 mg/kg dose and PBS (A) Change from baseline in average distance run per night (B) Change from baseline in average time run per night (C) Change from baseline in average speed per night.

Fig. 2

Voluntary wheel cage activity for C57BL/6 and MCP-1^−/− mice following treatment with 5-fluororacil. Data are presented as percent change from baseline (mean ± SE). *p < 0.05 between WT-60 and WT-PBS, #p < 0.05 between WT-60 and MCP-1^−/−-60, $p < 0.05 between MCP-1^−/−-60 and MCP-PBS. (A) Change from baseline in average distance run per night. (B) Change from baseline in average time run per night. (C) Change from baseline in average speed per night.