ABSTRACT
The use of prior exercise training has shown promise in minimizing doxorubicin (DOX)-induced physical impairments. The purpose of this study was to compare changes in thymus mass, thymocyte (T-cell) number, and tissue peroxidation following chronic endurance exercise and DOX treatment in the rat. The thymus mass, number of viable T-cells, and levels of malondialdehyde and 4-hydroxyalkenals (MDA+4-HAE) were compared 3 days post-injection between rats assigned to the following treatment conditions: (a) 10 weeks of endurance training, followed by a saline injection 24 hours after the last training session (TM+SAL); (b) treadmill training as above, followed by a single, bolus 10-mg/kg injection of DOX (TM+10); (c) treadmill training with 12.5 mg/kg of DOX (TM+12.5); (d) sedentary (without exercise) and a saline injection (SED+SAL); (e) sedentary with 10 mg/kg of DOX (SED+10); and (f) sedentary with 12.5 mg/kg (SED+12.5). Thymic mass and T-cell numbers significantly decreased following DOX injections. TM rats exhibited significantly less lipid peroxidation compared with paired-dose SED groups. TM+10 did not significantly differ from SED+SAL in thymic levels of lipid peroxidation. We conclude that chronic endurance exercise decreases levels of lipid peroxidation in the thymus seen with acute DOX treatment.
Subject(s)
Doxorubicin/adverse effects , Drug-Related Side Effects and Adverse Reactions/physiopathology , Physical Conditioning, Animal/physiology , Physical Endurance/physiology , Thymocytes/drug effects , Thymus Gland/drug effects , Animals , Exercise Therapy/methods , Lipid Peroxidation/drug effects , Male , Rats , Rats, Sprague-Dawley , T-Lymphocytes/drug effectsABSTRACT
1. Doxorubicin (DOX) is a highly effective and commonly used anthracycline antibiotic used to treat cancer patients. The side effects of DOX are manifested in a more delayed manner in children and multidrug resistant proteins (MRPs) may factor into this phenomenon. MRPs are known to extrude DOX and may factor into the degree of cardiac DOX accumulation. 2. The purpose of this study was to examine age-related differences in muscle MRP expression and DOX accumulation. 3. Female Sprague-Dawley rats were randomly selected to receive a 15-mg DOX/kg body weight bolus injection (i.p.) at various ages. 4. Cardiac and extensor digitorum longus DOX accumulation was markedly increased as animals aged from 4 to 24 weeks. In contrast, no differences in soleus accumulation were observed. A significant age-related reduction in MRP-2 and MRP-7 expression was detected in cardiac and extensor digitorum longus tissues with no age differences in MRP-1 expression in any tissues analyzed. MRP-6 was not detected in any tissues. 5. These data suggest that aging is associated with increased DOX accumulation and an age-related decrease in MRP expression may be a factor.
Subject(s)
Doxorubicin/pharmacokinetics , Multidrug Resistance-Associated Proteins/metabolism , Muscle, Skeletal/metabolism , Myocardium/metabolism , Age Factors , Animals , Female , Heart/drug effects , Heart/physiology , Muscle, Skeletal/drug effects , Rats , Rats, Sprague-Dawley , Tissue DistributionABSTRACT
Doxorubicin (DOX) is a highly effective anthracycline antibiotic used to treat a wide array of cancers. Its use is limited because of dose-dependent cardiovascular toxicity. Although exercise training has been shown to protect against DOX-induced cardiotoxicity, it is unclear as to whether exercise can attenuate DOX-induced vascular dysfunction. The purpose of this study was to determine if exercise training provides protection against the deleterious vascular effects of DOX treatment and if any changes in vascular function are related to the accumulation of DOX in vascular tissue. Male Sprague-Dawley rats remained sedentary (SED) or engaged in 14 weeks of voluntary wheel running (WR). After the 14-week period, animals received 15 mg DOX per kilogram of body mass or an equivalent volume of saline. Twenty-four hours after DOX/saline exposure, the aorta was isolated and was used to examine vascular function and aortic DOX accumulation. Aortic rings from WR + DOX animals contracted with significantly greater force and showed improved endothelium-independent relaxation when compared with rings from SED + DOX animals. In contrast, no significant differences in endothelium-dependent aortic function were noted between WR + DOX and SED + DOX. Furthermore, no significant differences in aortic DOX accumulation were observed between the DOX groups. These results suggest that chronic exercise attenuates vascular smooth muscle dysfunction associated with DOX treatment and seems to be independent of DOX accumulation in vascular tissue.
