title: Doxorubicin ototoxicity is induced in mice by combination treatment with cyclosporin A.
abstract: Although doxorubicin [adriamycin (ADM)] ototoxicity has not been detected to date, it has been reported that neurotoxicity in the central nervous system was induced by chemotherapy with ADM in patients receiving chronic cyclosporin A (CsA) treatment. ADM ototoxicity may be induced by combination therapy with CsA because extrusion of ADM from the inner ear by p-glycoprotein (p-gp), which acts as an extrusion pump and is expressed on the surface of endothelial cells of capillary blood vessels, might be inhibited by CsA. resulting in significant accumulation of ADM in the inner ear. ADM (10 mg/kg) was administered to FVB mice either with or without CsA (200 mg/kg). Auditory brainstem responses (ABRs) were recorded before and after treatment. ABR changes were not observed in mice treated with either ADM or CsA alone. Threshold elevation, elongation of wave I-V latencies and interpeak latencies of waves I-II, I-III, I-IV and I-V were detected in mice treated with ADM in combination with CsA. These changes reached their peak values 3 weeks after treatment, and then recovered to pre-treatment levels. In normal mice, ADM is extruded by p-gp from the inner ear and auditory pathway, thus preventing hearing disorder. However, ADM ototoxicity was induced by combination therapy with CsA, indicating that CsA has an inhibitory action on p-gp function in the auditory pathway, including the inner ear. After organ transplantation, therefore, clinical administration of ADM in combination with CsA should be performed with caution.
authors.affiliation: Department of Otolaryngology, Fukui Medical University, Yoshida-gun, Japan. takehisa@fmsrsa.fukui-med.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Tokuriki
authors.forename: Y
authors.initials: Y
authors.lastname: Shibamori
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: I
authors.initials: I
authors.lastname: Noda
authors.forename: T
authors.initials: T
authors.lastname: Ohtsubo
authors.forename: H
authors.initials: H
authors.lastname: Saito
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D001309:Auditory Threshold / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004317:Doxorubicin / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D007758:Ear, Inner / Q000187:drug effects / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D006311:Hearing Disorders / Q000139:chemically induced / Q000517:prevention & control; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D004317:Doxorubicin; D016572:Cyclosporine