Ototoxicity from cisplatin

Auditory brainstem responses have been used to detect ototoxicity from cisplatin and carboplatin when used in combination therapy (95). 

Auditory brainstem responses have been used to detect ototoxicity from cisplatin and carboplatin when used in combination therapy (95). The method can detect early high frequency damage due to these drugs up to two or three cycles earlier than conventional audiometry. 

Therapeutic applications Cisplatin has found wide application in the treatment of solid tumors such as metastatic testicular carcinoma in combination with vinblastine (see p. 390) and bleomycin (see p. 386), ovarian carcinoma in combination with cyclophosphamide (see p. 388), or alone for bladder carcinoma. Carboplatin is employed when patients cannot be vigorously hydrated as is required for cisplatin treatment, or if they suffer from kidney dysfunction or are prone to neuro- or ototoxicity. 

Mr AC s renal function is reduced, as can be observed from the high serum urea and creatinine levels and low EDTA clearance. Each of the three drugs used in the BEP regimen are renally excreted. In particular the excretion of cisplatin is largely dependant on the kidneys and deterioration in renal function is directly related to the development of acute toxicity (e.g. nephrotoxicity, ototoxicity). 

Using a similar approach to our studies of cisplatin-induced ototoxicity, we have identified a series of SNPs associated with anthrac-yline-induced cardiotoxicity in children with cancer in Canada, a finding that we have verified in a replication cohort from the Netherlands [69, 70]. We identified a series of risk and protective alleles that can be related at least in good part to the known pharmacology of the anthracyclines these variants include protective variants characterized by loss-of-function for influx transporters for anthracyclines as well as risk variants characterized by loss-of-function for efflux transporters for anthracyclines (Table 2, Fig. 5) [69],... 

Since the above ototoxins have other targets than cochlear/ vestibular hair cells, the requirements of in vitro models for these drugs differ from models for permanent hair cell loss by cisplatin and AGs. Consequently, in vitro models for furosemide and quinine ototoxicity require the experimental assessment of the lateral wall, not so much of the organ of Corti or the vestibular organs. The action of salicylate may be studied in organ of Corti explants that allow for analysis of hair cells. 

To what extent cell lines from the Immorto-Mouse are appropriate inner ear models and thus are useful for ototoxic studies is a matter of debate. On the positive side, the OC-k3 cell line displayed cisplatin-induced apoptotic cell death that was attenuated by inhibition of mitogen-activated protein kinase kinases [86, 87], HEI-OC1 cells were sensitive to gentamicin, streptomycin, cispla-tin, and acetaminophen/hydrocodon [40, 85], However, the HEI-OC1 cell line received some criticism lately, because of the absence of cell death in response to gentamicin [77, 88], These characteristics suggested that the ototoxin-sensitivity of HEI-OC1 depended on the culturing conditions, or that some cell batches had lost their sensitivity to AG-induced cell death. 

Aside from general caveats that apply to many in vitro models, there is one concern specific to research on AGs and cisplatin. Their mechanisms of toxicity involve the formation of ROS and are therefore sensitive to the antioxidant capacity of the incubation medium. This parameter is rarely controlled and different standard media contain varying amounts of redox-active amino acids, glutathione, or other compounds. Even the common pH indicator phenol red is an important contributor to the total antioxidant capacity of cell and tissue culture media [97]. Thus, the antioxidative capacity of the incubation media may differ from the endolymph and comparable media need to be used to compare therapeutic efficiencies. The concern applies not only to studies of ototoxic mechanisms of these drugs but perhaps even more also to attempts to identify protective treatments which most frequently include therapeutics with antioxidant properties. 

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