Characterization of mitoxantrone cardiotoxicity in cultured heart cells.
AuthorShipp, Nancy Gillett
AdvisorDorr, Robert T.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractThe use of the anthracenedione mitoxantrone as an antitumor agent is steadily increasing. While the toxicities associated with its use are significantly less than those observed following treatment with the widely used doxorubicin, mitoxantrone cardiotoxicity is clearly a substantial clinical problem. Current information on the mechanism by which mitoxantrone causes toxicity in heart tissue is limited. Thus, the goal of these studies was to describe a model system in which mitoxantrone cardiotoxicity can be studied, and begin to describe the mechanism by which mitoxantrone exerts its cardiotoxic effect. These experiments have shown that cultured neonatal rat heart cells are an effective model system for studying mitoxantrone-induced cytotoxicity and biochemical changes in heart tissue. Cultured heart cells develop dose- and time-dependent toxicity following a short exposure to near-pharmacologically achievable drug concentrations. Furthermore, histologic changes characteristic of this drug are also observed at the light and electron microscopic level. Initial experiments aimed at defining mitoxantrone mechanism of action showed that mitoxantrone likely does not stimulate a significant production of active oxygen species, or have a specific effect on mitochondrial function. However, there is evidence to support the possibility that mitoxantrone can form a reactive intermediate in vitro. These studies have shown that covalent binding of mitoxantrone to proteins can occur under certain conditions. Mitoxantrone toxicity is lowered with the addition of ICRF-187, a metal chelating agent. Protection is not due to inactivation of mitoxantrone, decreased mitoxantrone uptake, or a delayed increase in cytosolic calcium. Similar protection is observed against doxorubicin and the oxidized form of mitoxantrone, but not against the non-hydroxylated analog of mitoxantrone, ametantrone. Furthermore, in a cell-free system, mitoxantrone can form complexes with both copper (II) and iron (III). Mitoxantrone metal binding is reversible as ICRF-187 as well as other chelators can remove the metals from these complexes. These data suggests that metal chelation is involved in the enhancement of mitoxantrone toxicity in vitro.
Degree ProgramPharmacology and Toxicology