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dc.contributor.authorPlummer, E Ruth
dc.contributor.authorMiddleton, Mark R
dc.contributor.authorJones, Christopher
dc.contributor.authorOlsen, Anna
dc.contributor.authorHickson, Ian
dc.contributor.authorMcHugh, Peter
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorMcGown, Gail
dc.contributor.authorThorncroft, Mary R
dc.contributor.authorWatson, Amanda J
dc.contributor.authorBoddy, Alan V
dc.contributor.authorCalvert, A Hilary
dc.contributor.authorHarris, Adrian L
dc.contributor.authorNewell, David R
dc.contributor.authorCurtin, Nicola J
dc.date.accessioned2009-08-04T17:28:41Z
dc.date.available2009-08-04T17:28:41Z
dc.date.issued2005-05-01
dc.identifier.citationTemozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1. 2005, 11 (9):3402-9 Clin. Cancer Res.en
dc.identifier.issn1078-0432
dc.identifier.pmid15867241
dc.identifier.doi10.1158/1078-0432.CCR-04-2353
dc.identifier.urihttp://hdl.handle.net/10541/76293
dc.description.abstractPURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.
dc.language.isoenen
dc.subjectCancer Metastasisen
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshAged, 80 and over
dc.subject.meshAntineoplastic Agents, Alkylating
dc.subject.meshComet Assay
dc.subject.meshDNA Damage
dc.subject.meshDNA Methylation
dc.subject.meshDNA Repair
dc.subject.meshDNA, Neoplasm
dc.subject.meshDacarbazine
dc.subject.meshFemale
dc.subject.meshHeadache
dc.subject.meshHumans
dc.subject.meshLymphocytes
dc.subject.meshMale
dc.subject.meshMelanoma
dc.subject.meshMiddle Aged
dc.subject.meshNeoplasm Metastasis
dc.subject.meshNeutropenia
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase
dc.subject.meshPoly(ADP-ribose) Polymerases
dc.subject.meshThrombocytopenia
dc.subject.meshTime Factors
dc.subject.meshTreatment Outcome
dc.titleTemozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.en
dc.typeArticleen
dc.contributor.departmentNorthern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom. E.R.Plummer@ncl.ac.uken
dc.identifier.journalClinical Cancer Researchen
html.description.abstractPURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.


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