■ OBJECTIVES: Cisplatin is an effective antineoplastic agent with dose-limiting nephrotoxicity and ototoxicity. Cisplatin lesions DNA and contributes to oxidative stress by depleting thiols such as glutathione. Repair of cisplatin-DNA adducts by nucleotide excision repair (NER) mechanisms and activation of antioxidant systems ameliorate cisplatin induced cytotoxicity. This study examined the order of activation of two major NER proteins, xeroderma pigmentosum complementation group A and C (XPA and XPC) and two antioxidant response proteins, transient receptor potential cation channel subfaimily V1 (TRPV1) and mitochondrial uncoupling protein 2 (UCP2) in spiral ganglion cells following two cycles of low level cisplatin exposure.

■ METHODS: Adult female Fisher 344 rats were given two, 4 day treatment cycles (1 mg/kg twice daily, cisplatin or saline control, i.p.) separated by 10 days of rest. Hydration therapy (10 ml/day saline, s.c.) prevented nephrotixicity. Subgroups of 10 treated and saline control rats were euthanized on days 5, 19 and 22. Paraffin-embedded decalcified temporal bone sections (8mu) were stained immunohistochemically with polyclonal antibodies against XPA, XPC, UCP2 and TRPV1, and visualized with standard ABC-peroxidase methods.

■ RESULTS: The cisplatin treated rats displayed an increased proportion of spiral ganglion cells with nuclear expression of XPC at day 5 and XPA at days 5 and 19 (p <0.05 re:controls). The proportion of TRPV1 and UCP2-immunoreactive spiral ganglion cells in the cisplatin-treated groups were elevated on days 19 and 22 (p <0.01 re: controls), but not on day 5.

■ CONCLUSIONS: Nuclear translocation of XPC and XPA occurs with a 2 hour rate constant after DNA damage,lesion occupancy also has a 2 hour rate constant. Hence, the day 5 XPC and XPA nuclear  translocations indicate on-going global genomic NER of cisplatin- DNA adducts. The XPA nuclear translocation and increased UCP2 and TRPV1 expression on day 19 suggest a shift to transcription-coupled NER and responses to oxidative stress, respectively. The latter response persists on day 22. These findings suggest that NER pathways and antioxidant systems operate in parallel to promote spiral ganglion cell survival in the face of DNA damage and thiol depletion after cisplatin exposure.