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Ototoxicity of Carboplatin Delivered Locally in a Monkey Brainstem

Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

T. Cooper

Department of Comparative Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

G. I. Jallo
B. S. Carson, Sr.
M. Guarnieri

Department of Neurological Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

Correspondence: Address correspondence to M. Guarnieri, Department of Neurological Surgery, Johns Hopkins School of Medicine, 600 N. Wolfe Street, Suite 811 Harvey, Baltimore, MD 21287-8811, USA. E-mail:mguarnie{at}jhmi.edu

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 µl/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.

Key Words: Brain Tumor Therapy • Carboplatin • Hair Cells • Local Delivery • Ototoxicity • Support Cells

International Journal of Toxicology, Vol. 24, No. 6, 443-449 (2005)
DOI: 10.1080/10915810500368951


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