Breast cancer patients treated with anthracycline chemotherapeutics such as doxorubicin (DOX) have increased risk of cardiomyopathy. Studies suggest that exercise training (ET) might increase the efficacy of DOX and reduce its cardiotoxic effect, but ET effects on tumor and cardiac pathophysiology are not yet fully known. This thesis aimed to elucidate the effects of voluntary wheel running ET during DOX treatment on the tumor growth and DOX induced cardiotoxicity. The thesis focused particularly on the ET induced alterations in the tumor and heart glucose uptake, mitochondrial metabolism, and blood flow.

Female FVB-mice subcutaneously inoculated with I3TC-mammary tumor cells or saline were given running wheels with DOX or saline treatment. The heart function was measured at baseline and after two (T2) and four DOX doses (T3). Heart and tumor glucose uptake were measured with positron emission tomography (PET) at T2 and T3. Tumor blood flow and blood mean transit time (MTT) were measured with PET at T2. Several molecular variables were also measured from the tumors and hearts. The Study I showed that ET inhibits tumor growth by increasing tumor apoptosis without vascular normalization. ET also increased left ventricle (LV) capillarity and lactate dehydrogenase (LDH) activity. Study II revealed that DOX reduced over time mouse running activity, body weight, LV mass, ejection fraction, LV capillarity and mitochondrial coupling, and increased LV glucose uptake. ET ameliorated all of these changes except body weight loss and capillary rarefaction. Furthermore, ET increased LV citrate synthase activity of all mice and decreased LV LDH activity in DOX treated mice. Study III revealed that a longer time period ET with lower running activity than in Study I reduces tumor metabolic volume, maximum glucose uptake without affecting total lesion glycolysis, mitochondrial function or tumor growth. Initially at T2 ET without DOX reduced tumor MTT, blood vessel α-smooth muscle actin coverage, larger vessel density and caused a trend towards improved blood flow, but vascular changes did not persist until T3. This thesis clearly reveals beneficial effects of ET on tumor and heart glucose uptake and blood flow warranting further studies with more effective DOX treatment and more intense ET, particularly regarding tumor effects.