AbstractsBiology & Animal Science

Pharmacokinetics and inner ear transport of cisplatin

by Victoria Hellberg

Institution: Karolinska Institute
Year: 2015
Record ID: 1332556
Full text PDF: http://hdl.handle.net/10616/44503


Background Cisplatin is a commonly used platinum anti-cancer drug. Regrettably cisplatin has dose-limiting ototoxic side effects, e.g. the drug can induce an irreversible hearing loss. The ototoxic mechanisms of cisplatin have not been elucidated in the human ear and no clinically useful oto-protectors are yet available. Cisplatin is a necessary part of many treatment regimes. Its beneficial therapeutic effects might be reduced if cisplatin was excluded from the treatment in order to protect the hearing function. In this work the ototoxic effects of cisplatin are studied with the aim to better understand the mechanisms behind the irreversible hearing loss induced by this drug. Oxaliplatin is a second generation platinum-derivative anti-cancer drug, free from ototoxic side effects in clinical practice. The effects of oxaliplatin on the inner ear have been studied in this work and the results are compared with cisplatin treatment. The two drugs differ regarding both anti-cancer effects and side effects, which could be attributed to differences in pharmacokinetic factors, cellular uptake and apoptotic mechanisms. The thioredoxin redox system with the enzyme thioredoxin reductase (TrxR) was studied in cochleae due to a suggested DNA-independent apoptotic mechanism of the hair cells. The cochlear pharmacokinetics of cisplatin was assessed and the transport protein organic cation transporter 2 (OCT2) was studied in relation to the ototoxic effect of cisplatin. Material and methods Cultured human colon carcinoma cells and cell cultures of rat organ of Corti were used for apoptosis studies in vitro following exposure to cisplatin and oxaliplatin. Cisplatin and oxaliplatin were administered i.v. to guinea pigs, followed by in vivo sampling of blood, cerebrospinal fluid (CSF) and scala tympani (ST) perilymph. Liquid chromatography with post-column derivatization was used to determine the concentration of parent drug in the samples. Electrophysiological hearing thresholds and the loss of hair cells were assessed to evaluate their ototoxic effects. Phenformin, a potential blocker of OCT2 was administered and the ototoxic side effect of cisplatin was evaluated. For immunohistochemical studies, cochlea from rat, guinea pig and pig were used, where TrxR and OCT2 were evaluated in the cochlea. TrxR-assays were used to measure the TrxR activity in cochlear tissue, both in vivo and in vitro. Results The results from the in vitro studies showed that addition of either cisplatin or oxaliplatin to the culture medium in organ of Corti cell cultures caused a similar amount of outer hair cell loss and inhibition of TrxR activity. Cisplatin exposure to cultured human colon carcinoma cells also reduced the activity of TrxR. The results from the in vivo studies showed that a considerable concentration of cisplatin was present in ST perilymph as compared with weak concentrations of oxaliplatin after high dose oxaliplatin i.v. Ten minutes after cisplatin administration, its concentration in ST perilymph was 4-fold higher in the basal…