Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. The purpose of this study was to examine the effects of low-intensity exercise training (LIET) during the course of Dox treatment on cardiac function, myosin heavy chain expression, oxidative stress, and apoptosis activation following treatment. Male Sprague-Dawley rats either remained sedentary or were exercise trained on a motorized treadmill at 15 m/min, 20 min/day, 5 days/wk (Monday through Friday) for 2 wk. During the same 2-wk period, Dox (2.5 mg/kg) or saline was administered intraperitoneally to sedentary and exercised rats 3 days/wk (Monday, Wednesday, Friday) 1-2 h following the exercise training sessions (cumulative Dox dose: 15 mg/kg). Five days following the final injections, hearts were isolated for determination of left ventricular (LV) function, lipid peroxidation, antioxidant enzyme protein expression, 72-kDa heat shock protein expression, caspase-3 activity, and myosin heavy chain isoform expression. Dox treatment significantly impaired LV function and increased caspase-3 activity in sedentary animals (P < 0.05). LIET attenuated the LV dysfunction and apoptotic signal activation induced by Dox treatment and increased glutathione peroxidase expression, but it had no significant effect on lipid peroxidation, protein expression of myosin heavy chain isoforms, 72-kDa heat shock protein, or superoxide dismutase isoforms. In conclusion, our data suggest that LIET applied during chronic Dox treatment protects against cardiac dysfunction following treatment, possibly by enhancing antioxidant defenses and inhibiting apoptosis.

Endurance training prior to DOX treatment protects against acute DOX cardiotoxicity for up to 10 d, and this protection can potentially be explained by a preservation of MHC isoform distribution.

These data suggest that the cardioprotective effects of exercise against DOX-induced injury may be due, in part, to a reduction in myocardial DOX accumulation.

Doxorubicin treatment alone (SED+DOX) promoted a significant decline in end-systolic pressure (-35%), left ventricular developed pressure (-59%), and the maximal rate of left ventricular pressure development (-43%) as well as a 45% increase in lipid peroxidation products when compared with SED+SAL (P<.05). Acute exercise 24 hours before DOX treatment, however, had a cardioprotective effect, as end-systolic pressure, left ventricular developed pressure, and the maximal rate of left ventricular pressure development were significantly higher in EX+DOX compared with SED+DOX (P<.05) and EX+DOX had similar levels of lipid peroxidation products as SED+SAL CONCLUSIONS: An acute exercise bout performed 24 hours before DOX treatment protected against cardiac dysfunction, and this exercise-induced cardioprotection may partly be explained by a reduction in the generation of reactive oxygen species.

Acute doxorubicin (DOX) cardiotoxicity can be attenuated by exercise preconditioning, but little is known of whether this cardioprotection continues beyond 10 days post-DOX administration. The purpose of this study was to determine the effects of exercise preconditioning on early chronic DOX-induced cardiotoxicity. Male rats were randomly assigned to sedentary, treadmill, or wheel running groups. Treadmill and wheel running animals participated in a progressive treadmill training protocol or voluntary wheel running, respectively, for 10 weeks. Following the intervention, animals were further randomized to receive either DOX (sedentary + DOX, treadmill + DOX, wheel running + DOX) or saline (sedentary + saline, treadmill + saline, wheel running + saline). All animals then remained sedentary for 4 weeks. A 22% reduction in fractional shortening was observed in left ventricles from previously sedentary animals receiving DOX when compared with sedentary + saline. This degree of decline was not observed in treadmill + DOX and wheel running + DOX. Sedentary + DOX possessed significantly depressed mitral and aortic valve blood flow velocities when compared with sedentary + saline, but these decrements were not observed in treadmill + DOX and wheel running + DOX. Ex vivo analysis revealed that left ventricular developed pressure and maximal rate of pressure development were significantly lower in sedentary + DOX when compared to sedentary + saline. Treadmill and wheel running prior to DOX treatment protected against these decrements. Exercise cardioprotection was associated with preserved myosin heavy chain but not sarcoendoplasmic reticulum Ca 2+ ATPase 2a expression. In conclusion, 10 weeks of prior exercise protected against early chronic DOX cardiotoxicity suggesting that training status may be a determining factor in the degree of late-onset cardiotoxicity experienced by cancer patients undergoing treatment with DOX.

Purpose/Objectives-To investigate the effects of supervised exercise training on cardiopulmonary function and fatigue in cancer survivors undergoing various clinical treatments. Design-Pretest and post-test quasiexperimental.Setting-Outpatient oncology rehabilitation center. Sample-96 breast cancer survivors undergoing various clinical treatments.Methods-Subjects were divided into four groups based on the specific type of clinical treatment: surgery alone (n = 22); surgery and chemotherapy (n = 30); surgery and radiation (n = 17); and surgery, chemotherapy, and radiation (n = 27). Following a comprehensive screening and medical examination, cardiovascular endurance, pulmonary function, and fatigue were assessed, leading to the development of an individualized exercise prescription and a six-month exercise intervention. Repeated-measures analysis of variance and covariance were used to compare the effectiveness of the intervention and differences among treatment groups.Main Research Variables-Systolic and diastolic blood pressure, resting heart rate, forced vital capacity, forced expiratory volume, predicted oxygen consumption, time on treadmill, and fatigue.Findings-Cardiopulmonary function (predicted maximal oxygen consumption and time on treadmill) significantly increased in all groups after exercise training. In addition, resting heart rate and forced vital capacity significantly improved in those receiving surgery, chemotherapy, and radiation. Psychologically, the exercise intervention resulted in significant reductions in behavioral, affective, sensory, cognitive and mood, and total fatigue scale scores in all three groups who received treatment with surgery. The breast cancer survivors in the surgery-alone group showed significant reductions in behavioral, affective, and total fatigue scale scores but not in sensory and cognitive and mood fatigue scale scores.

Exercise training, initiated at the time treatment begins, can protect against delayed-onset anthracycline-induced cardiotoxicity in adult rats that were treated with anthracyclines as juveniles.

Cancer-related fatigue is a pervasive syndrome experienced by a majority of cancer patients undergoing treatment, and muscular dysfunction may be a key component in the development and progression of this syndrome. Doxorubicin (DOX) is a commonly used antineoplastic agent used in the treatment of many cancers. The purpose of this study was to determine the effect of DOX exposure on the function of cardiac, skeletal, and smooth muscle tissues and examine the role accumulation of DOX may play in this process. In these studies, rats were treated with DOX and measurements of cardiac, skeletal, and smooth muscle function were assessed 1, 3, and 5 days after exposure. All muscular tissues showed significant and severe dysfunction, yet there was heterogeneity both in the time course of dysfunction and in the accumulation of DOX. Cardiac and skeletal muscle exhibited a time-dependent progressive decline in function during the 5 days following DOX treatment. In contrast, vascular function showed a decline in function that could be characterized as rapid onset and was sustained for the duration of the 5-day observation period. DOX accumulation was greatest in cardiac tissue, yet all muscular tissues showed a similar degree of dysfunction. Our data suggest that in muscular tissues both DOX-dependent and DOX-independent mechanisms may be involved with the muscular dysfunction observed following DOX treatment. Furthermore, this study highlights the fact that dysfunction of skeletal and smooth muscle may be an underappreciated aspect of DOX toxicity and may be a key component of cancer-related fatigue in these patients.