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 doxorubicin (DXR) and cardiac irradiation (IRR) could precipitate the unexpected expression of congestive heart failure. Oxidative lesions induced by IRR and DXR could represent one of the pathogenic factors of myocardial dysfunction. Our investigations were performed to evaluate in the rat: 1) cardiac functional changes, 2) cardiac and plasma peroxidative damage and antioxidant 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 irradiation exerted no detectable effect. Antioxidant defenses disturbances in hearts of DXR treated rats were characterized by vitamins C and E decreases, catalase activity induction and an increase in lipid peroxidation. Moreover, plasma vitamin C consumption and the lower level of plasma lipid peroxidation attested to the efficient solicitation of antioxidant defenses that probably contributed to the preservation of cardiac function at 24 h. After 30 d, cardiac dysfunction became symptomatic at rest, resulting from DXR cardiac toxicity. In spite of the persistent activation of cardiac catalase activity, antioxidant deficiency and increased plasma and cardiac lipid peroxidation highlighted defenses overtaken. Thus, different physiopathological mechanisms are involved in heart disturbance at acute and middle terms, IRR 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. Oxidative damage to the heart induced both by irradiation and DXR, may be one of the pathogenic factors of myocardial dysfunction. There is the possibility that the deleterious effects might be limited by the use of pharmacologic antioxidant agents.
Dalloz
F
F
Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaires Expérimentales, Facultés de Médecine et de Pharmacie, Dijon, France. rochette@u-bourgogne.fr
Maingon
P
P
Cottin
Y
Y
Briot
F
F
Horiot
J C
JC
Rochette
L
L
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001205:Ascorbic Acid / Q000378:metabolism; D001794:Blood Pressure; D002374:Catalase / Q000378:metabolism; D003037:Cobalt Radioisotopes; D003683:Dehydroascorbic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D005720:Gamma Rays; D005979:Glutathione Peroxidase / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects / Q000528:radiation effects; D066298:In Vitro Techniques; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D014810:Vitamin E / Q000378:metabolism
D000975:Antioxidants; D003037:Cobalt Radioisotopes; D014810:Vitamin E; C000820:semidehydroascorbic acid; D004317:Doxorubicin; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid