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- Hellberg, VictoriaKarolinska Institutet (author)
Cisplatin and oxaliplatin toxicity : importance of cochlear kinetics as a determinant for ototoxicity
- Article/chapterEnglish2009
Publisher, publication year, extent ...
- 2008-12-30
- Cary :Oxford University Press,2009
- printrdacarrier
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- LIBRIS-ID:oai:DiVA.org:umu-18621
- https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-18621URI
- https://doi.org/10.1093/jnci/djn418DOI
- http://kipublications.ki.se/Default.aspx?queryparsed=id:118085755URI
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- Language:English
- Summary in:English
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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 and genre
- MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
- MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng
- mammalian thioredoxin reductase
- sulfur-containing compounds
- guinea pig
- molecular mechanisms
- monohydrated complex
- cerebrospinal fluid
- active site
- cell-death
- pharmacokinetics
- apoptosis
Added entries (persons, corporate bodies, meetings, titles ...)
- Wallin, Inger (author)
- Eriksson, SofiKarolinska Institutet (author)
- Hernlund, Emma (author)
- Jerremalm, Elin (author)
- Berndtsson, MariaKarolinska Institutet (author)
- Eksborg, StaffanKarolinska Institutet (author)
- Arnér, Elias SJ (author)
- Shoshan, MariaKarolinska Institutet (author)
- Ehrsson, Hans (author)
- Laurell, GöranKarolinska Institutet,Umeå universitet,Öron- näs- och halssjukdomar,Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden(Swepub:umu)gala0001 (author)
- Karolinska InstitutetÖron- näs- och halssjukdomar (creator_code:org_t)
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- In:Journal of the National Cancer InstituteCary : Oxford University Press101:1, s. 37-470027-88741460-2105
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