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

• Published in: JNCI : Journal of the National Cancer Institute 2009-01, Vol.101 (1), p.37-47
• Main Authors: Hellberg, Victoria, Wallin, Inger, Eriksson, Sofi, Hernlund, Emma, Jerremalm, Elin, Berndtsson, Maria, Eksborg, Staffan, Arnér, Elias S. J., Shoshan, Maria, Ehrsson, Hans, Laurell, Göran
• Format: Article
• Language: English
• Subjects: active site; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; apoptosis; Apoptosis - drug effects; Area Under Curve; Biological and medical sciences; Calcium - metabolism; Carcinoma - drug therapy; Carcinoma - metabolism; Carcinoma - pathology; cell-death; cerebrospinal fluid; Chelating Agents - pharmacology; Chemotherapy; Chromatography, Liquid; Cisplatin - administration & dosage; Cisplatin - adverse effects; Cisplatin - pharmacokinetics; Cochlea - drug effects; Cochlea - metabolism; Cochlear Diseases - chemically induced; Cochlear Diseases - metabolism; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Comparative studies; Confidence Intervals; Disease Models, Animal; Drug toxicity and drugs side effects treatment; Ears & hearing; Female; Free Radical Scavengers - pharmacology; guinea pig; Guinea Pigs; Hair Cells, Auditory - drug effects; Hair Cells, Auditory - metabolism; HCT116 Cells; Humans; Immunohistochemistry; Infusions, Intravenous; Kinetics; Male; mammalian thioredoxin reductase; Mass Spectrometry - methods; Medical sciences; Medicin och hälsovetenskap; molecular mechanisms; monohydrated complex; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - adverse effects; Organoplatinum Compounds - pharmacokinetics; Oxaliplatin; Oxidants - metabolism; Perilymph - drug effects; Perilymph - metabolism; pharmacokinetics; Pharmacology. Drug treatments; Scala Tympani - drug effects; Scala Tympani - metabolism; Signal Transduction - drug effects; sulfur-containing compounds; Superoxides - metabolism; Thioredoxin-Disulfide Reductase - metabolism; Toxicity: respiratory system, ent, stomatology; Toxicology; Tumors
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djn418

Background Cisplatin 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. Methods In 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. Results In 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. Conclusion Cisplatin- 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.