Cytoprotective agents for anthracyclines.

摘要: Anthracycline-induced cardiotoxicity is believed to be related the generation of reactive oxygen species by at least two mechanisms: enzymatic reduction quinone with subsequent redox cycling and/or formation an iron-anthracycline complex capable intramolecular and cycling. Both pathways may lead production superoxide anions highly metabolites, such as hydroxyl radicals hydrogen peroxide. As a result, membrane lipid peroxidation ensue, producing damage in tissues like heart, which have low antioxidant defenses (superoxide dismutase glutathione especially, glutathione-peroxidase). Pharmacologic methods interrupting this cycle involved numerous antioxidants, sulfhydryls N-acetylcysteine cysteamine, lipophilic vitamin alpha tocopherol. Unfortunately, none these compounds has been proven cardioprotective patients receiving doxorubicin. In contrast, water-soluble d-isomer iron chelator razoxane, dexrazoxane or ICRF-187, shown reduce doxorubicin-induced cardiomyopathy. This afforded greater cumulative doses doxorubicin safely administered. The cytoprotective effect apparently limited heart since there no on antitumor efficacy and, unfortunately, gastrointestinal toxicity, slight increase myelosuppression. More recent preclinical studies also demonstrated activity for aminothiol amifostine (WR-2721). vitro, agent scavenge radicals, latter mediated active (dephosphorylated) metabolite, WR-1065. tumor-bearing mice, reduces lethality high without affecting activity. Finally, vitro neonatal rat cells direct evidence anthracycline cardioprotection both Cytoprotective drug levels either were 2.0 microg/mL, one tenth achievable peak plasma humans. At concentration, 15-minute sulfhydryl pretreatment significantly prevented depressions myocyte adenosine triphosphate levels. Overall, suggest that against cardiac damage. Animal chronically dosed model are indicated; if positive, clinical trials testing hypothesis will warranted.