Cytoprotective agents for anthracyclines

Research output: Contribution to journalArticle

133 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)23-34
Number of pages12
JournalSeminars in Oncology
Volume23
Issue number4 SUPPL. 8
StatePublished - Oct 7 1996

ASJC Scopus subject areas

  • Hematology
  • Oncology

Fingerprint Dive into the research topics of 'Cytoprotective agents for anthracyclines'. Together they form a unique fingerprint.

  • Cite this