Effects of combined irradiation and doxorubicin treatment on cardiac function and antioxidant defenses in the rat

Combined radiotherapy and chemotherapy have represented a major advance in the therapeutic management of cancer therapy. However, the combination of d oxorubicin (DXR) and cardiac irradiation (IRR) could precipitate the unexpe cted expression of congestive heart failure. Oxidative lesions induced by I RR and DXR could represent one of the pathogenic factors of myocardial dysf unction. Our investigations were performed to evaluate in the rat: 1) cardi ac functional changes, 2) cardiac and plasma peroxidative damage and antiox idant defenses variations, that occur 24 h (acute effects) and 30 d (middle term effects) following DXR treatment 1 mg/kg(-1)/day(-1) IP for 10 d and a 1 x 20 Gy cardiac gamma-irradiation. Our results showed that DXR affected heart reactivity as early as the end of its administration, although irrad iation exerted no detectable effect. Antioxidant defenses disturbances in h earts of DXR treated rats were characterized by vitamins C and E decreases, catalase activity induction and an increase in lipid peroxidation. Moreove r, plasma vitamin C consumption and the lower level of plasma lipid peroxid ation attested to the efficient solicitation of antioxidant defenses that p robably contributed to the preservation of cardiac function at 23 h. After 30 d, cardiac dysfunction became symptomatic at rest, resulting from DXR ca rdiac toxicity. In spite of the persistent activation of cardiac catalase a ctivity, antioxidant deficiency and increased plasma and cardiac lipid pero xidation highlighted defenses overtaken. Thus, different physiopathological mechanisms are involved in heart disturbance at acute and middle terms, IR R and DXR acting on distinct targets without disclosing synergistic effects , After 30 d, cardiac and plasma biochemical abnormalities were emphasized by the combined DXR+IRR therapy, pointing out the severity of the damage. O xidative damage to the heart induced both by irradiation and DXR, may be on e of the pathogenic factors of myocardial dysfunction. There is the possibi lity that the deleterious effects might be limited by the use of pharmacolo gic antioxidant agents. (C) 1999 Elsevier Science Inc.