Cisplatin and Oxaliplatin Toxicity: Importance of Cochlear Kinetics as a Determinant for Ototoxicity

Abstract

BackgroundCisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.MethodsIn HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration–time curve (AUC). Statistical tests were two-sided.ResultsIn HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 μM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 μg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 μM × minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics.ConclusionCisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.

Proposed comprehensive ototoxicity monitoring program for VA healthcare (COMP-VA)

“…This damage occurs in a relatively orderly manner of base (high frequency) to apex (low frequency) destruction [10] primarily of the outer hair cells, which are sensory receptor cells that provide for the large dynamic range and exacting frequency selectivity that characterizes human hearing. Damage also occurs to the marginal cells of the stria vascularis [11][12][13][14], which provides the electrochemical drive for the outer hair cells and spiral ganglion cells of the auditory nerve. A main mechanism of cisplatin ototoxicity is associated with the production of free radicals [15].…”

Audiological Monitoring in Children Treated with Platinum Chemotherapy

“…Furthermore, carboplatin is considered less ototoxic than cisplatin at standard doses, but when it is administered in combination with cisplatin or osmotic agents or as myelosuppressive regimen, the incidence of ototoxicity increases [Bertolini et al, 2004]. Finally, the third-generation platinum compound oxaliplatin seems to be responsible for lower-grade cochlear toxicity compared to cisplatin and carboplatin although few studies have been published [Hellberg et al, 2009]. Several lines of research have been focused on the mechanism of platinum-derived ototoxicity.…”

Oxaliplatin and ototoxicity: is it really safe for hearing?

“…In a study by Hellberg et al, oxaliplatin was found to have minimal ototoxicity, and they attributed this to limited cochlear uptake of oxaliplatin (16).…”