Received for publication January 6, 2006.
Revised March 28, 2006.
Accepted for publication March 28, 2006.

High accumulation of platinum-DNA adducts in strial marginal cells of the cochlea is an early event in cisplatin but not carboplatin ototoxicity

Abstract

Ototoxicity is a typical dose-limiting side effect of cancer chemotherapy with cisplatin but much less with carboplatin. To elucidate the underlying molecular pathomechanisms we have measured the formation and persistence of drug-induced DNA adducts in the nuclei of inner ear cells of guinea pigs after acute exposure to either cis- or carboplatin using immunofluorescence staining and quantitative image analysis. After application of carboplatin, all cells of the cochlea exhibited a similar burden of guanine-guanine intrastrand crosslinks in DNA. In contrast, we observed a pronounced 3- to 5-fold accumulation of this cytotoxic adduct exclusively in the marginal cells of the stria vascularis between 8 to 48 hours after treatment with cisplatin. In the kidney, the other critical target tissue of cisplatin toxicity, a similar high preferential formation of cytotoxic DNA adducts was measured in the tubular epithelial cells but not in other renal cell types. As for the ear, this excessive formation of DNA damage in a particular cell type was seen in cisplatin- but not in carboplatin-treated animals. Since cisplatin ototoxicity is often attributed to oxidative stress mediated by the generation of radical oxygen species (ROS), we have measured in parallel the levels of the lead DNA oxidation product 8-oxoguanine (8-oxoG) in cochlear cryosections. Compared to basal levels in untreated controls, no additional formation of 8-oxoG was detectable up to 48 h after cisplatin treatment in the DNA of either inner ear cell type. This suggests that the generation of ROS may be a secondary event in cisplatin ototoxicity.

Key words: Immunocytochemistry, Antibody, Apoptosis, DNA damage and repair, Oxidative stress, Mechanisms of cell killing/apoptosis, Pharmacokinetics, metabolism and activation

This article has been cited by other articles:

				A. Dzagnidze, Z. Katsarava, J. Makhalova, B. Liedert, M.-S. Yoon, H. Kaube, V. Limmroth, and J. Thomale Repair Capacity for Platinum-DNA Adducts Determines the Severity of Cisplatin-Induced Peripheral Neuropathy J. Neurosci., August 29, 2007; 27(35): 9451 - 9457. [Abstract] [Full Text] [PDF]