Cisplatin and oxaliplatin toxicity: importance of cochlear kinetics as a determinant for ototoxicity.
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 HCT-116 cells, cisplatin (20 microM)-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 HCT-116 cells, cisplatin (20 microM)-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 microM)-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 microg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 microM 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.


CONCLUSIONS
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.
Hellberg
Victoria
V
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. victoria.hellberg@karolinska.se
Wallin
Inger
I
Eriksson
Sofi
S
Hernlund
Emma
E
Jerremalm
Elin
E
Berndtsson
Maria
M
Eksborg
Staffan
S
Arnér
Elias S J
ES
Shoshan
Maria
M
Ehrsson
Hans
H
Laurell
Göran
G
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects*; D019540:Area Under Curve; D002118:Calcium / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002614:Chelating Agents / Q000494:pharmacology; D002853:Chromatography, Liquid; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism*; D015834:Cochlear Diseases / Q000139:chemically induced* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016001:Confidence Intervals; D004195:Disease Models, Animal; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006168:Guinea Pigs; D045325:HCT116 Cells; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000077150:Oxaliplatin; D016877:Oxidants / Q000378:metabolism; D010498:Perilymph / Q000187:drug effects / Q000378:metabolism; D012533:Scala Tympani / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism
D000970:Antineoplastic Agents; D002614:Chelating Agents; D016166:Free Radical Scavengers; D009944:Organoplatinum Compounds; D016877:Oxidants; D000077150:Oxaliplatin; D013481:Superoxides; D013880:Thioredoxin-Disulfide Reductase; D002945:Cisplatin; D002118:Calcium