Influence of N-acetylcysteine on the antitumor activity of doxorubicin.

Abstract

C ONSIDERABLE ATTENTION has been given to doxorubicin-induced cardiomyopathy since its recognition nearly 10 yr ago. Although the mechanism by which doxorubicin (DOX) produces cardiotoxicity is unknown, evidence suggests that it is linked to the effect of free radicals formed during the drug’s metabolism’ (Fig. 1). Handa and Sate* initially showed that DOX metabolism in a microsomal NADPH oxidase system yielded superoxide anion (0;;). Goodman and Hochstein3 demonstrated that, in the reduction-oxidation cycle of DOX 1 molecule in the quinone form could cycle to a semiquinone then back to the quinone form many times to generate molecules of superoxide anion and initiate lipid peroxidation. When Bachur et aL4 demonstrated that heart microsomes from rats were capable of supporting the generation of free radicals from DOX, it was suggested that a free radical oxidative mechanism might mediate the cardiotoxicity of this drug. This concept was supported by data from Myers et al.’ and Olson et al.6 demonstrating that the antioxidant vitamin E and the free radical scavenger cysteamine attenuated the acute cardiotoxicity of DOX in mice. The glutathione peroxidase pathway (Fig. 2), which detoxifies potentially damaging peroxides by reducing them to alcohols, also was shown to be an important modulator of DOX-induced cardiotoxicity.‘.’ Depletion of endogenous glutathione by diethyl maleate’.’ and inhibition of glutathione peroxidase by reduction of endogenous selenium stores (selenium is a required cofactor of glutathione peroxidase activity)‘dramatically potentiated DOX-induced cardiotoxicity in laboratory animals. Furthermore, pretreatment of rabbits with diethyl maleate to lower endogenous cardiac glutathione levels to less than 30% of basal values significantly potentiated the negative inotropic activity of DOX in isolated papillary muscles obtained from pretreated rabbits.’ Additionally, studies with Nacetylcysteine (NAC) have shown this agent to provide significant protection against DOXinduced cardiotoxicity.“,”