Effects of Verapamil on the Acute Toxicity of Doxorubicin In Vivo

Abstract

Background : Studies indicating that verapamil substantially enhances doxorubicin levels in certain drug-resistant tumor cells have led to the use of verapamil in combination with doxorubicin in animal and clinical studies of multidrug-resistant tumors. These studies have shown this drug combination to be associated with severe toxic effects. It is important to determine whether verapamil modulates the dose-limiting and potentially lethal cardiotoxicity of doxo-rubicin and to elucidate possible mechanisms. Purpose : The aims of this study were to evaluate the in vivo effects of verapamil on ( a ) doxorubicin-stimulated cardiac lipid peroxidation and cardiac damage, ( b ) doxorubicin-induced animal mortality, and ( c ) biodistribution of doxorubicin to the heart. Methods : Male (BALB/c × DBA/2)F ₁ mice were treated with a high dose of doxorubicin (15 mg/kg, injected intraperitoneally), verapamil (25 mg/kg, injected intraperitoneally), or combinations of the two. Lipid peroxidation was determined using the 2-thiobarbituric acid assay for malonaldehyde. Light microscopy was used for histopathologic examination of cardiac tissue. A fluorometric assay procedure was employed to determine doxorubicin levels in the heart. Results : Verapamil was an effective inhibitor of peroxidative damage to myocardial lipids following a high dose of doxorubicin (15 mg/kg, injected intraperitoneally). However, mice treated with verapamil and doxorubicin had a lower survival rate and a higher initial peak concentration of doxorubicin in the heart than those treated with doxorubicin alone. They also demonstrated a higher incidence and severity of degenerative changes in cardiac tissue. Conclusions : Our findings suggest that verapamil effectively inhibits doxorubicin-mediated lipid peroxidation in vivo but that cardiac lipid peroxidation is not the major limiting mechanism underlying doxorubicin-induced toxicity. A possible explanation for the excess mortality and cardiac injury in mice treated with verapamil plus doxorubicin is that verapamil alters the pharmacokinetics of doxorubicin. Implications : Further studies are necessary for development of safer protocols and/or drug combinations to treat multidrug-resistant tumors. We are currently studying treatment of tumor-bearing animals with a cumulative dosage regimen of doxorubicin in the presence and absence of verapamil. [J Natl Cancer Inst 84: 1653–1660, 1992]