Journal of the National Cancer Institute Advance Access originally published online on December 30, 2008
JNCI Journal of the National Cancer Institute 2009 101(1):37-47; doi:10.1093/jnci/djn418
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ARTICLES |
Cisplatin and Oxaliplatin Toxicity: Importance of Cochlear Kinetics as a Determinant for Ototoxicity
Affiliations of authors: Department of Clinical Neuroscience (VH, GL), Department of Oncology and Pathology (EH, EJ, MB, MS, HE), Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics (SE, ESJA), and Childhood Cancer Research Unit, Department of Woman and Child Health (SE), Karolinska Institutet, Stockholm, Sweden; Karolinska Pharmacy, Karolinska University Hospital, Stockholm, Sweden (IW, EJ, SE, HE); Department of Clinical Sciences, Umeå University, Umeå, Sweden (GL)
Correspondence to: Victoria Hellberg, MD, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (e-mail: victoria.hellberg{at}karolinska.se).
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 x 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.
| CONTEXT AND CAVEATS Prior knowledge Chemotherapy with cisplatin is often associated with hearing loss (ie, ototoxicity), but treatment with oxaliplatin, another platinum-based chemotherapeutic agent, is rarely associated with ototoxic side effects. Study design A cancer cell line was used to investigate whether inhibitors of superoxide- and calcium-mediated signaling could alter cisplatin- or oxaliplatin-induced apoptosis. A guinea pig model was used to examine cisplatin- or oxaliplatin-induced ototoxicity and pharmacokinetics of both drugs in the cochlea. Contribution In cancer cells, cisplatin-induced apoptosis, but not oxaliplatin-induced apoptosis, was reduced by lowering the concentration of calcium ions or superoxide ions. In guinea pig cochlea, total and perilymphatic drug concentrations were lower after oxaliplatin treatment than after cisplatin treatment and appear to be a major explanation for its lower ototoxicity. Implications Additional research is warranted into the mechanisms of how treatment with cisplatin vs oxaliplatin leads to ototoxicity. Limitations It is not clear how cytotoxicity in cancer cells relates to ototoxicity in vivo. Drug concentrations in the perilymph over time could not be measured in an individual guinea pig because only one sample can be taken from each cochlea. Human subjects and guinea pigs may or may not have the same cochlear pharmacokinetics. From the Editors
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Manuscript received December 3, 2007; revised October 7, 2008; accepted October 20, 2008.
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J Natl Cancer Inst 2009 101: 1.