Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39–45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination.
Exercise has long been known to be beneficial to human health. Studies aimed at understanding the effects of exercise specifically focus on predetermined exercise intensities defined by measuring the aerobic capacity of each individual. Many disease models involving animal training often establish aerobic capacity by using the maximal lactate steady state (MLSS), a widely used method in humans that has frequently been used in rodent studies. The MLSS is defined as the highest exercise intensity at which blood lactate concentration remains constant and is roughly equivalent to 70–80% of maximal aerobic capacity. Due to our up-coming experiments investigating the effect of different exercise intensities in specific strains of tumor-bearing mice, the aim of the present study was to determine the MLSS in athymic nude (NCr nu/nu and NMRI), CDF1, and C3H mice by treadmill running at increasing speeds. However, despite thorough exercise acclimation and the use of different exercise protocols and aversive stimuli, less than half of the experiments across strains pointed towards an established MLSS. Moreover, gently prodding the mice during low to moderate intensity running caused a 30–121% (p<0.05) increase in blood lactate concentration compared to running without stimulation, further questioning the use of lactate as a measure of exercise intensity. Overall, MLSS is difficult to determine and large variations of blood lactate levels were observed depending on the exercise protocol, mice handling strategy and strain. This should be considered when planning experiments in mice using forced exercise protocols.
Objectives: The objectives were to investigate 1) the effect of acute aerobic exercise on tumour hypoxia and blood perfusion, 2) the impact of exercise intensity, 3) the duration of the effect, and 4) the effect of prolonged training on tumour hypoxia as well as tumour growth. Methods: Female CDF1 mice were inoculated with the C3H mammary carcinoma either in the mammary fat pad or subcutaneously in the back. For experiments on the effect of different intensities in a single exercise bout, mice were randomized to 30 min treadmill running low, moderate, or high intensity speeds or no exercise. To investigate the prolonged effect on hypoxia and tumour growth, tumour-bearing mice were randomized to no exercise (CON) or daily 30 min high-intensity exercise averaging two weeks (EX). Tumour hypoxic fraction was quantified using the hypoxia marker Pimonidazole. Results: Initially, high intensity exercise reduced tumour hypoxic fraction by 37% compared with CON (p=0.046; 95% CI: 0.1; 10.3) in fat pad tumours. Low and moderate intensities did not. Following experiments investigating the duration of the effect - as well as experiments in mice with back tumours - failed to show any exercise induced changes in hypoxia. Interestingly, prolonged daily training significantly reduced hypoxic fraction by 60% (p=0.002; 95% CI: 2.5;10.1) compared with CON. Conclusion: Despite diverging findings on the acute effect of exercise on hypoxia, our data indicate that if exercise has a diminishing effect, high-intensity exercise is needed. Prolonged training reduced tumour hypoxic fraction - cautiously suggesting a potential clinical potential.
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