O6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: results of a phase II study.

2.50
Hdl Handle:
http://hdl.handle.net/10541/86677
Title:
O6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: results of a phase II study.
Authors:
Middleton, Mark R; Lee, Siow Ming; Arance, Ana; Wood, Michelle; Thatcher, Nick; Margison, Geoffrey P
Abstract:
O6-Methylguanine-DNA methyltransferase (MGMT) is a major determinant of resistance to temozolomide. Its levels are depleted in lymphocytes after drug administration, but there is partial recovery by 24 hr, the usual time of subsequent dosing. Administering subsequent doses of temozolomide at the MGMT nadir could enhance its effectiveness, by increasing the amount of O6-methylguanine (O6-meG) in DNA. We evaluated the efficacy of such a schedule of temozolomide and determined the kinetics of MGMT depletion and O6-meG formation in DNA following treatment. Thirty patients with advanced malignant melanoma were treated with temozolomide 1,000 mg/m2 equally split into 5 doses over a 16 hr period every 28 days. O6-meG formation was determined in peripheral blood mononuclear cell (PBMC) DNA and, in a subset of patients, in tumor tissue during the first treatment cycle. MGMT levels fell rapidly with dosing, reaching a nadir in PBMCs of 18.0 +/- 2.26% of initial levels. O6-meG levels increased during the treatment period, peaking at 11.1 +/- 1.25 micromol/mol dG in PBMCs and at 4.25 +/- 0.79 micromol/mol dG in tumor biopsies. The main toxicities were grade IV thrombocytopenia in 12 patients (42.8%) and grade IV neutropenia in 11 patients (39.2%), associated with fever in 8 cases. There were 7 responses (1 complete), for an overall response rate of 23.3%; median overall survival was 6.1 months. The compressed schedule has activity against melanoma, with greater MGMT depletion and O6-meG formation than previously reported for O6-alkylating agent regimens. Myelosuppression precludes its wider application, but MGMT in PBMCs predicted the dose intensity of temozolomide that patients could sustain, suggesting a means by which individuals suitable for this approach might be identified.
Affiliation:
Cancer Research Campaign Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK. mmiddleton@picr.man.ac.uk
Citation:
O6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: results of a phase II study. 2000, 88 (3):469-73 Int. J. Cancer
Journal:
International Journal of Cancer
Issue Date:
1-Nov-2000
URI:
http://hdl.handle.net/10541/86677
DOI:
10.1002/(SICI)1097-0215(20000115)85:2<248::AID-IJC16>3.0.CO;2-V
PubMed ID:
11054678
Type:
Article
Language:
en
ISSN:
0020-7136
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorMiddleton, Mark Ren
dc.contributor.authorLee, Siow Mingen
dc.contributor.authorArance, Anaen
dc.contributor.authorWood, Michelleen
dc.contributor.authorThatcher, Nicken
dc.contributor.authorMargison, Geoffrey Pen
dc.date.accessioned2009-11-23T11:08:06Z-
dc.date.available2009-11-23T11:08:06Z-
dc.date.issued2000-11-01-
dc.identifier.citationO6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: results of a phase II study. 2000, 88 (3):469-73 Int. J. Canceren
dc.identifier.issn0020-7136-
dc.identifier.pmid11054678-
dc.identifier.doi10.1002/(SICI)1097-0215(20000115)85:2<248::AID-IJC16>3.0.CO;2-V-
dc.identifier.urihttp://hdl.handle.net/10541/86677-
dc.description.abstractO6-Methylguanine-DNA methyltransferase (MGMT) is a major determinant of resistance to temozolomide. Its levels are depleted in lymphocytes after drug administration, but there is partial recovery by 24 hr, the usual time of subsequent dosing. Administering subsequent doses of temozolomide at the MGMT nadir could enhance its effectiveness, by increasing the amount of O6-methylguanine (O6-meG) in DNA. We evaluated the efficacy of such a schedule of temozolomide and determined the kinetics of MGMT depletion and O6-meG formation in DNA following treatment. Thirty patients with advanced malignant melanoma were treated with temozolomide 1,000 mg/m2 equally split into 5 doses over a 16 hr period every 28 days. O6-meG formation was determined in peripheral blood mononuclear cell (PBMC) DNA and, in a subset of patients, in tumor tissue during the first treatment cycle. MGMT levels fell rapidly with dosing, reaching a nadir in PBMCs of 18.0 +/- 2.26% of initial levels. O6-meG levels increased during the treatment period, peaking at 11.1 +/- 1.25 micromol/mol dG in PBMCs and at 4.25 +/- 0.79 micromol/mol dG in tumor biopsies. The main toxicities were grade IV thrombocytopenia in 12 patients (42.8%) and grade IV neutropenia in 11 patients (39.2%), associated with fever in 8 cases. There were 7 responses (1 complete), for an overall response rate of 23.3%; median overall survival was 6.1 months. The compressed schedule has activity against melanoma, with greater MGMT depletion and O6-meG formation than previously reported for O6-alkylating agent regimens. Myelosuppression precludes its wider application, but MGMT in PBMCs predicted the dose intensity of temozolomide that patients could sustain, suggesting a means by which individuals suitable for this approach might be identified.en
dc.language.isoenen
dc.subjectAlkylating Anticancerous Agentsen
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAged, 80 and over-
dc.subject.meshAntineoplastic Agents, Alkylating-
dc.subject.meshDacarbazine-
dc.subject.meshDrug Administration Schedule-
dc.subject.meshFemale-
dc.subject.meshGuanine-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMelanoma-
dc.subject.meshMiddle Aged-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.titleO6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: results of a phase II study.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK. mmiddleton@picr.man.ac.uken
dc.identifier.journalInternational Journal of Canceren

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