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WFRF:(Hellberg Maria)
 

Sökning: WFRF:(Hellberg Maria) > Cisplatin and oxali...

  • Hellberg, VictoriaKarolinska Institutet (författare)

Cisplatin and oxaliplatin toxicity : importance of cochlear kinetics as a determinant for ototoxicity

  • Artikel/kapitelEngelska2009

Förlag, utgivningsår, omfång ...

  • 2008-12-30
  • Cary :Oxford University Press,2009
  • printrdacarrier

Nummerbeteckningar

  • 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

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Wallin, Inger (författare)
  • Eriksson, SofiKarolinska Institutet (författare)
  • Hernlund, Emma (författare)
  • Jerremalm, Elin (författare)
  • Berndtsson, MariaKarolinska Institutet (författare)
  • Eksborg, StaffanKarolinska Institutet (författare)
  • Arnér, Elias SJ (författare)
  • Shoshan, MariaKarolinska Institutet (författare)
  • Ehrsson, Hans (författare)
  • Laurell, GöranKarolinska Institutet,Umeå universitet,Öron- näs- och halssjukdomar,Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden(Swepub:umu)gala0001 (författare)
  • Karolinska InstitutetÖron- näs- och halssjukdomar (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Journal of the National Cancer InstituteCary : Oxford University Press101:1, s. 37-470027-88741460-2105

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