Polyoxyethylene‐modified Superoxide Dismutase Reduces Side Effects of Adriamycin and Mitomycin C

Abstract

Polyoxyethylene‐modified superoxide dismutase (SOD‐POE) is a newly developed long‐acting superoxide dismutase. Adriamycin (ADR) and mitomycin C (MMC) generate superoxide, which contributes to their cytocidal effects or side effects. We examined whether SOD‐POE could prevent the side effects induced by superoxide generated by antitumor agents, and the following results were obtained. SOD‐POE did not influence the antitumor effects of ADR and MMC either in vitro or in vivo, but prevented the toxic death of BALB/c, nu/nu male mice caused by overdoses of ADR or MMC. As for its effective sites, SOD‐POE prevented a decrease in the specific activity of rotenone‐sensitive NADH‐ubiquinone oxidoreductase (complex I) in heart muscle mitochondrial respiratory chain function in BALB/c male mice administered 10 mg/kg ADR, and prevented damage to the sarcoplasmic reticulum and mitochondria of mouse heart muscle by ADR as observed by electron microscopy. Furthermore, SOD‐POE prevented bone marrow suppression induced by MMC in Donryu rats. The above results suggest that combination chemotherapy with SOD‐POE would make it possible to increase the maximum permissible doses of antitumor agents, improving the efficacy of these agents.

Recommendations for genetic testing to reduce the incidence of anthracycline‐induced cardiotoxicity

“…Use of other cardioprotective agents (level C recommendation). Other cardioprotective drugs such as L-carnitine, probucol, deferoxamine, ethylenediaminetetraacetic acid (EDTA), coenzyme Q10, N-acetylcysteine, vitamin E, digoxin, enalapril, phenethylamines, superoxide dismutase, monohydroxyethylrutoside and other ACE inhibitors or beta-blockers have demonstrated significant cardioprotective effects [99][100][101][102][103][104][105][106][107][108][109][110] but have been less well investigated compared to dexrazoxane. RCTs have been performed for some of these agents [82,103,[111][112][113][114].…”

Cardiomyopathies: Evolution of pathogenesis concepts and potential for new therapies

“…It is the only approved cardioprotective agent in anthracycline chemotherapy, but there is no evidence for a difference in response rate or survival [54] . Other agents such L-carnitine, coenzyme Q10, N-acetylcysteine, vitamin E, and trimetazidine, have been investigated as metabolic cardioprotective agents [55][56][57][58][59][60][61][62] . Unfortunately, none of them showed prominent clinical efficacy in preventing anthracycline toxicity.…”

Endocannabinoid Inhibition

“…That cardiomyocytes may be particularly susceptible to doxorubicin's free radical effects may be partially explained by data showing that cardiomyocytes have low levels of catalase activity (10), that myocardial glutathione peroxidase decreases after doxorubicin administration (11), and that doxorubicin undergoes redox cycling in mitochondria, increasing the generation of free radicals. The high volume fraction of mitochondria in the heart may thus be linked to its vulnerability, because mitochondria are one of the major targets of doxorubicin's toxicity (12)(13)(14)(15). Additional differences between the response of cancer versus myocardial cells to doxorubicin may be explained by signaling pathways that play opposing roles depending on the cell type in which they are acting; for example, in myocytes doxorubicin-induced activation of nuclear factor-kappa B is proapoptotic, whereas in cancer cells nuclear factor-kappa B is antiapoptotic.…”