title: Ototoxicity of carboplatin delivered locally in a monkey brainstem.
abstract: Ototoxicity is a common side effect of platinum-based chemotherapy. Intratumoral drug delivery theoretically could reduce the ototoxic effects of systemic drug infusions. However, local delivery to central nervous system (CNS) tumors might promote ototoxicity through drug release into cerebrospinal fluid (CSF). This report describes an examination of the cytoarchitecture of vestibular cells of cynomolgus monkeys that had chronic brainstem infusions with the maximum tolerated dose (MTD) of carboplatin. The brainstems of adult monkeys were infused for 30 days at 0.42 mu l/h with 0.025 to 0.25 mg/kg (MTD) of carboplatin. The vestibular sensory epithelia of eight drug-treated animals were isolated for microscopic examination of vestibular hair cells and support cells. Local infusions produced chronic elevated CSF levels of platinum, neurological symptoms, and radiographic evidence of pontine injury. Histology revealed significant cell damage at the infusion sites. Microscopic examinations of vestibular support cells and hair cells demonstrate a small reduction in cell counts in the drug-treated monkeys compared to a noninfused control animal. Parametric and nonparametric tests show no effect of dose in predicting the vestibular cell counts. In this single study of eight monkeys, a dose-dependent reduction of vestibular hair cells or support cells was not observed in animals infused with brainstem infusions of 0.025 to 0.25 mg/kg of carboplatin.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins School of Medicine, 600 N. Wolfe Street, Suite 811 Harvey, Baltimore, MD 21287-8811, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Carey
authors.forename: T
authors.initials: T
authors.lastname: Cooper
authors.forename: G I
authors.initials: GI
authors.lastname: Jallo
authors.forename: B S
authors.initials: BS
authors.lastname: Carson
authors.forename: M
authors.initials: M
authors.lastname: Guarnieri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001933:Brain Stem / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002452:Cell Count; D018069:Hair Cells, Vestibular / Q000187:drug effects / Q000473:pathology; D034381:Hearing Loss / Q000139:chemically induced / Q000473:pathology; D007260:Infusion Pumps; D008252:Macaca fascicularis; D008297:Male; D020714:Maximum Tolerated Dose; D009336:Necrosis; D010984:Platinum / Q000097:blood / Q000134:cerebrospinal fluid; D011859:Radiography; D012665:Semicircular Canals / Q000187:drug effects / Q000473:pathology; D013194:Staining and Labeling; D014722:Vestibule, Labyrinth / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D010984:Platinum; D016190:Carboplatin