Sequential administration of temozolomide and fotemustine: depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours.
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State: Public
Version: Final published version
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It was possible to publish this article open access thanks to a Swiss National Licence with the publisher.
UNIL restricted access
State: Public
Version: Final published version
License: Not specified
It was possible to publish this article open access thanks to a Swiss National Licence with the publisher.
Serval ID
serval:BIB_6B773617CF43
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Sequential administration of temozolomide and fotemustine: depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours.
Journal
Annals of oncology
ISSN
0923-7534 (Print)
ISSN-L
0923-7534
Publication state
Published
Issued date
07/1999
Peer-reviewed
Oui
Volume
10
Number
7
Pages
831-838
Language
english
Notes
Publication types: Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
The DNA repair protein O6-alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitrosoureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloroethylnitrosoureas. We report the results of a dose finding study of TMZ in association with fotemustine.
Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m2, divided over two days. Fotemustine 100 mg/m2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics.
The maximum tolerated dose (MTD) of TMZ was 400 mg/m2 (200 mg/m2/d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs.
PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.
Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m2, divided over two days. Fotemustine 100 mg/m2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics.
The maximum tolerated dose (MTD) of TMZ was 400 mg/m2 (200 mg/m2/d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs.
PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.
Keywords
Adult, Aged, Antineoplastic Combined Chemotherapy Protocols/administration & dosage, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Brain Neoplasms/blood, Brain Neoplasms/drug therapy, Brain Neoplasms/enzymology, Dacarbazine/administration & dosage, Dacarbazine/adverse effects, Dacarbazine/analogs & derivatives, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Resistance, Neoplasm, Female, Glioma/blood, Glioma/drug therapy, Glioma/enzymology, Humans, Lymphocytes/enzymology, Male, Melanoma/blood, Melanoma/drug therapy, Melanoma/enzymology, Middle Aged, Nitrosourea Compounds/administration & dosage, Nitrosourea Compounds/adverse effects, O(6)-Methylguanine-DNA Methyltransferase/blood, Organophosphorus Compounds/administration & dosage, Organophosphorus Compounds/adverse effects, Temozolomide
Pubmed
Web of science
Open Access
Yes
Create date
28/01/2008 9:31
Last modification date
06/08/2024 7:02