While many drugs cause adverse side-effects cancer chemotherapies can be particularly severe. This is not lost on scientists and physicians. The biggest challenge in fighting cancer is that the disease is a part of the patient. Human cells and bacterial cells are very different making it easier to find compounds that kill the disease but not the patient – things are not so different between cancerous and healthy human cells. Thus many chemotherapies are basically poisons that happen to affect tumors a bit more aggressively. Scientists are currently working hard to develop new therapies that are more specifically targeted thus having less toxicity, and clinicians have found amazing ways to mitigate symptoms from side effects. Nonetheless, cancer survivors often face unique challenges and needs that do not receive the attention society gives to finding and improving cures. To meet this need, Dr. Karen Syrjala works with mouse models to understand the long-term effects of cancer chemotherapy. A recent collaboration between Fred Hutch (Clinical Research, Public Health Sciences, and Human Biology Divisions) and University of Washington researchers focused on the effects of cyclophosphamide treatment. Cyclophosphamide is used both as chemotherapy and as an immune suppressant during transplants making it particular pertinent here at Fred Hutch. In a PLoS One publication these researchers focused on how cyclophosphamide contributes to one of the most common long-term symptoms reported for cancer survivors – fatigue.
For this study mice were treated with a single high dose of cyclophosphamide. This treatment caused a 5% decrease in body weight, consistent with the side effects caused by many chemotherapies. The cyclophosphamide treated mice recovered to the body weight of control, saline treated mice in about 25 days. To understand the long-term effect of cyclophosphamide on skeletal muscle function, mice were placed on a treadmill and the total length of time they were able to run was measured prior to treatment. Mice were treated with saline or cyclophosphamide and allowed to recover for 6 weeks (nearly double the time required to recover body weight) before time spent on the treadmill was reassessed. While the saline group maintained the same fitness, the cyclophosphamide treated mice were able to run approximately 50% less, suggesting serious long term muscle fatigue. The researchers went on to characterize multiple mechanisms that may be contributing to the observed fatigue.
First, a minor loss (~10%) in leg muscle mass was observed in the cyclophosphamide treated mice as compared to saline treated mice. While this could be a contributing factor it suggested that more was at play, thus researchers tested the mitochondrial function in muscles of these mice. Mass spec studies on muscle tissue revealed that ATP levels were reduced one day following cyclophosphamide treatment and did not recover after six weeks. However, measuring the rate of oxidative phosphorylation revealed no difference suggesting ATP production was not affected by cyclophosphamide treatment. This suggests that some aspect of the ATP cycle was compromised, but perhaps not accounting for the entire fatigue phenotype.
Previous studies suggested that cyclophosphamide treatment causes an increase in reactive oxygen species that can cause DNA damage. This same phenomenon was observed in skeletal muscle one week after cyclophosphamide treatment, but did not persist for six weeks. Despite this increase, no mutations in mitochondrial DNA was observed.
This study identified a number of contributing factors that may result in long-term fatigue following cyclophosphamide treatment. Importantly this work was performed in adult mice, better representing the age at which most patients receive chemotherapy. A challenge to this model is that patients often receive weeks of dosing rather than a single one, thus follow up work is specifically focusing on a treatment profile that better matches one seen by breast cancer patients, as Dr. Karen Syrjala explained, “We have refined our mouse model to better reflect a clinical regimen by the addition of doxorubicin and multiple cycles of chemotherapy. In cancer patients, research has clearly established that exercise and in particular resistance training alleviates the fatigue and myopathies that otherwise persist long after treatment. With our current mouse model we are just starting a study on the impact of regular exercise and nutritional supplementation on chemotherapy-related muscle dysfunction. This study will also investigate the mechanisms by which cyclophosphamide and doxorubicin exposure leads to persistent muscle atrophy and dysfunction that we observe in our mice.” It is exciting to see more work focusing on survivorship and the challenges faced after beating cancer.
National Institutes of Health and Robert E. Frey funded this work.
Crouch M-L, Knowels G, Stuppard R, Ericson NG, Bielas JH, Marcinek DJ, Syrjala KL. 2017. Cyclophosphamide leads to persistent deficits in physical performance and in vivo mitochondria function in a mouse model of chemotherapy late effects. PLoS One, 12(7), e0181086.