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dc.contributor.authorBanerji, U
dc.contributor.authorWalton, M
dc.contributor.authorRaynaud, F
dc.contributor.authorGrimshaw, R
dc.contributor.authorKelland, L
dc.contributor.authorValenti, M
dc.contributor.authorJudson, I
dc.contributor.authorWorkman, P
dc.date.accessioned2018-06-25T14:22:19Z
dc.date.issued2005-10
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2005, 11 (19 Pt 1), pp. 7023 - 7032
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1910
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-05-0518
dc.description.abstractPurpose To establish the pharmacokinetic and pharmacodynamic profile of the heat shock protein 90 (HSP90) inhibitor 17-allylamino, 17-demethoxygeldanamycin (17-AAG) in ovarian cancer xenograft models.Experimental design The effects of 17-AAG on growth inhibition and the expression of pharmacodynamic biomarkers c-RAF-1, CDK4, and HSP70 were studied in human ovarian cancer cell lines A2780 and CH1. Corresponding experiments were conducted with established tumor xenografts. The variability and specificity of pharmacodynamic markers in human peripheral blood lymphocytes (PBL) were studied.Results The IC50 values of 17-AAG in A2780 and CH1 cells were 18.3 nmol/L (SD, 2.3) and 410.1 nmol/L (SD, 9.4), respectively. Pharmacodynamic changes indicative of HSP90 inhibition were demonstrable at greater than or equal the IC50 concentration in both cell lines. Xenograft experiments confirmed tumor growth inhibition in vivo. Peak concentrations of 17-AAG achieved in A2780 and CH1 tumors were 15.6 and 16.5 micromol/L, respectively, and there was no significant difference between day 1 and 11 pharmacokinetic profiles. Reversible changes in pharmacodynamic biomarkers were shown in tumor and murine PBLs in both xenograft models. Expression of pharmacodynamic markers varied between human PBLs from different human volunteers but not within the same individual. Pharmacodynamic biomarker changes consistent with HSP90 inhibition were shown in human PBLs exposed ex vivo to 17-AAG but not to selected cytotoxic drugs.Conclusion Pharmacokinetic-pharmacodynamic relationships were established for 17-AAG. This information formed the basis of a pharmacokinetic-pharmacodynamic-driven phase I trial.
dc.formatPrint
dc.format.extent7023 - 7032
dc.languageeng
dc.language.isoeng
dc.subjectLymphocytes
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectOvarian Neoplasms
dc.subjectLactams, Macrocyclic
dc.subjectBenzoquinones
dc.subjectRifabutin
dc.subjectProto-Oncogene Proteins c-raf
dc.subjectAntineoplastic Agents
dc.subjectBlotting, Western
dc.subjectTreatment Outcome
dc.subjectNeoplasm Transplantation
dc.subjectInhibitory Concentration 50
dc.subjectCell Proliferation
dc.subjectDose-Response Relationship, Drug
dc.subjectTime Factors
dc.subjectFemale
dc.subjectHSP70 Heat-Shock Proteins
dc.subjectHSP90 Heat-Shock Proteins
dc.subjectCyclin-Dependent Kinase 4
dc.subjectBiomarkers
dc.titlePharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models.
dc.typeJournal Article
rioxxterms.versionofrecord10.1158/1078-0432.ccr-05-0518
rioxxterms.licenseref.startdate2005-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue19 Pt 1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Sarcoma Clinical Trials
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Sarcoma Clinical Trials
pubs.publication-statusPublished
pubs.volume11
pubs.embargo.termsNot known
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
icr.researchteamMedicine Drug Development Unit (de Bono)en_US
icr.researchteamSarcoma Clinical Trialsen_US
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorBanerji, Udaien
dc.contributor.icrauthorWorkman, Paulen
dc.contributor.icrauthorJudson, Ianen
dc.contributor.icrauthorTurner, Lydiaen


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