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Cisplatin and oxali...
Cisplatin and oxaliplatin toxicity : importance of cochlear kinetics as a determinant for ototoxicity
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- Hellberg, Victoria (author)
- Karolinska Institutet
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Wallin, Inger (author)
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- Eriksson, Sofi (author)
- Karolinska Institutet
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Hernlund, Emma (author)
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Jerremalm, Elin (author)
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- Berndtsson, Maria (author)
- Karolinska Institutet
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- Eksborg, Staffan (author)
- Karolinska Institutet
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Arnér, Elias SJ (author)
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- Shoshan, Maria (author)
- Karolinska Institutet
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Ehrsson, Hans (author)
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- Laurell, Göran (author)
- Karolinska Institutet,Umeå universitet,Öron- näs- och halssjukdomar,Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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(creator_code:org_t)
- 2008-12-30
- 2009
- English.
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In: Journal of the National Cancer Institute. - Cary : Oxford University Press. - 0027-8874 .- 1460-2105. ; 101:1, s. 37-47
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Abstract
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- 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.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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- mammalian thioredoxin reductase
- sulfur-containing compounds
- guinea pig
- molecular mechanisms
- monohydrated complex
- cerebrospinal fluid
- active site
- cell-death
- pharmacokinetics
- apoptosis
Publication and Content Type
- ref (subject category)
- art (subject category)
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Hellberg, Victor ...
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Wallin, Inger
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Eriksson, Sofi
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Hernlund, Emma
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Jerremalm, Elin
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Berndtsson, Mari ...
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show more...
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Eksborg, Staffan
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Arnér, Elias SJ
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Shoshan, Maria
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Ehrsson, Hans
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Laurell, Göran
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show less...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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Journal of the N ...
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Umeå University
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Karolinska Institutet