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Distribution and toxic effects of intravenously injected epirubicin on the central nervous system of the mouse.

Epirubicin (4'-epi-doxorubicin) is a new anthracycline cytostatic, which was synthesized in an effort to find an agent with an improved therapeutic effect on human malignant tumours combined with reduced myocardial toxicity. Animal experiments have previously shown that the parent drug doxorubicin, besides being a myocardial toxin, may cause nerve cell lesions both in the central and the peripheral nervous system. Intravenously (i.v.) injected doxorubicin passes into regions of the nervous system located outside the blood-brain barrier (BBB); the drug accumulates in the nucleus of neurons and causes cell degeneration. This investigation was performed to establish whether epirubicin, given as a single i.v. injection in the mouse, could enter the central nervous system (CNS) and cause neurotoxic effects. Epirubicin was found to emit a primary orange fluorescence in thin frozen sections. Detectable amounts of epirubicin could not be seen in regions protected by the BBB. The choroid plexus and all the circumventricular brain regions with the exception of the subcommissural organ showed the presence of the drug in the parenchyma and a marked accumulation in cell nuclei. Severe cellular changes were found in these regions by light and electron microscopy and the alterations were most marked in mice with the longest survival period (45 days). The animals also developed a progressive sensory polyneuropathy and appeared lethargic. Epirubicin given as a single i.v. injection in the mouse will thus spread into brain regions lacking a BBB where it produces toxic lesions in the same way as previously reported for the parent compound, doxorubicin.