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.

Induction of IL-6 by Cytotoxic Chemotherapy Is Associated With Loss of Lean Body and Fat Mass in Tumor-free Female Mice

“…We showed previously that CAF increases MCP-1 levels in WT mice (Smith et al, 2014). In addition, Mahoney et al (2013) used MCP-1-deficient mice to show that a 5-FU-mediated decline in VWRA was MCP-1 dependent (Mahoney et al, 2013). …”

Dietary Quercetin Reduces Chemotherapy-Induced Fatigue in Mice

“…MCP-1 was measured in the plasma at baseline and at 5 days and 14 days post 5-FU. Previous work in this area has shown that increased levels of MCP-1 in the plasma are associated with fatigue following 5-FU chemotherapy 13 as well as other cytotoxic chemotherapies. 14 Likewise, MCP-1, in conjunction with other inflammatory cytokines, has been associated with increased fatigue in other chronic conditions including fibromyalgia 27 and chronic fatigue syndrome.…”

“…Consistent with this, we have reported that MCP-1-deficient mice have a heightened recovery from CIF as measured by voluntary wheel running activity. 13 There is also evidence that a diminished production of blood cells following chemotherapy treatment may contribute to CIF. In fact, a decrease in red blood cell production, leading to anemia, has been identified by the National Comprehensive Cancer Network as one of the treatable factors of CIF.…”

Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue

“…Numerous mouse models have been developed and used to recapitulate and better understand CRF produced by various causes, including chemotherapy [17–19], radiation [20], and cancer and cancer cachexia [21–23]. Given the many causes of CRF and the possibility that the underlying mechanisms of CRF may vary depending on the cause, it is important to determine if TAL has anti-fatigue effects in multiple models of CRF.…”

“…Thus, the current study used three mouse models of CRF. The first was a model of chemotherapy-induced fatigue, adapted from a published model [19]. The second was a mouse model of peripheral irradiation that causes fatigue-like behavior by mimicking the peripheral radiation exposure of radiation therapy [20].…”