Potentiation and protection of doxorubicin cytotoxicity by cellular glutathione modulation.

One of the proposed mechanisms of doxorubicin cytotoxicity is generation of activated oxygen species, all of which are either free radical or potentially free radical species. Glutathione is an intracellular sulfhydryl-containing tripeptide that is known to detoxify free radicals and the damage they produce. The cytotoxicity of doxorubicin was evaluated following treatment with agents that will either elevate intracellular glutathione (2-oxothiazolidine-4-carboxylate) or deplete intracellular glutathione levels correlate with doxorubicin cytotoxicity, ie, elevated glutathione provides protection and decreased glutathione levels increase cytotoxicity. These results are discussed in the context of cardiac toxicity as well as enhancing tumor cell kill with doxorubicin.