Abstract A28: A murine model for cancer treatment-related fatigue
Authors: Pouliot Kimberly L. , Alvarez Enrique , Watkins Brynmor , Fey Edward , Sonis Stephen 
Published: June 2012

Abstract
Objectives: Among patients being treated for cancer, cancer treatment-related fatigue (CTRF) remains a poorly understood condition with a profound effect on quality of life. Our objective was to develop a murine model of CTRF, independent of anemia, in order to further understand its pathogenesis and provide a conduit for the development of mechanistically-based therapeutic approaches.
Methods: To determine the optimal dose of ionizing radiation to produce fatigue, female BALB/c mice were irradiated with 10 doses of fractionated total body irradiation (fTBI, 8, 9, and 10 Gy, cumulative dose) or 15 doses (fTBI, 10.5 and 13.5 Gy, cumulative dose). In a separate experiment, mice received 70, 60 or 50 mg/kg of etoposide sulfate to determine the optimal dose of chemotherapy to induce CTRF. Cage-top activity sensors (Phillips Respironics) were used to evaluate daily activity patterns in animals up to 4 weeks following the completion of radiation or 12 weeks following etoposide sulfate administration. CTRF was induced by 15 doses of fractionated total body irradiation (fTBI, 10.5 Gy, cumulative dose) in female BALB/c mice or 60mg/kg etoposide sulfate administered as a single dose. Total daily animal activity and changes in wake/sleep cycles were compared to baseline levels. Systemic levels of IL-6 and TNF-α were measured and anemia and leukopenia were assessed using specimens obtained in the weeks following the last dose of radiation or etoposide sulfate administration.
Results: fTBI resulted in animals with a significantly lower cumulative daily activity, disrupted sleep/wake cycles that continued up to forty days following the last dose of radiation. Administration of etoposide sulfate resulted in a significantly lower cumulative daily activity three weeks following chemotherapy administration and continued for the duration of the study. Reduced activity levels were not associated with laboratory parameters suggestive of anemia. Changes in the measured hematological parameters demonstrated a temporal, dose-dependent and reversible pattern; consistent with those previously reported in human patients.
Conclusions: Despite its frequency and impact, CTRF has been accepted as a cost of successful cancer treatment. This conclusion was largely based on the supposition that, aside for symptom control, there was no opportunity to develop an effective intervention. We report the development a novel mouse model of CTRF in which administration of fractionated TBI or etoposide sulfate was able to induce behaviors consistent with fatigue reported in humans. Our data supports the hypothesis that TBI and chemotherapy induce systemic effects that result in changes in daily activity patterns and sleep/wake cycles in the absence of anemia. Consistent with reports in humans with fatigue syndromes, radiation-induced CTRF correlated with increased levels of TNF and IL-6. Additional work is ongoing to further characterize the model.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A28.