Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.

2.50
Hdl Handle:
http://hdl.handle.net/10541/76293
Title:
Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.
Authors:
Plummer, E Ruth; Middleton, Mark R; Jones, Christopher; Olsen, Anna; Hickson, Ian; McHugh, Peter; Margison, Geoffrey P; McGown, Gail; Thorncroft, Mary R; Watson, Amanda J; Boddy, Alan V; Calvert, A Hilary; Harris, Adrian L; Newell, David R; Curtin, Nicola J
Abstract:
PURPOSE: 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.
Affiliation:
Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom. E.R.Plummer@ncl.ac.uk
Citation:
Temozolomide 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.
Journal:
Clinical Cancer Research
Issue Date:
1-May-2005
URI:
http://hdl.handle.net/10541/76293
DOI:
10.1158/1078-0432.CCR-04-2353
PubMed ID:
15867241
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
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.en
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
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