Sequential administration of temozolomide and fotemustine: depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours

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Ressource 1Download: serval:BIB_6B773617CF43.P001 (2659.80 [Ko])
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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
Author(s)
Gander  M., Leyvraz  S., Decosterd  L., Bonfanti  M., Marzolini  C., Shen  F., Lienard  D., Perey  L., Colella  G., Biollaz  J., Lejeune  F., Yarosh  D., Belanich  M., D'Incalci  M.
ISSN
0923-7534 (Print)
Publication state
Published
Issued date
07/1999
Volume
10
Number
7
Pages
831-8
Notes
Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jul
Abstract
BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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/adverse effects/pharmacokinetics/pharmacology Brain Neoplasms/blood/drug therapy/enzymology Dacarbazine/administration & dosage/adverse effects/analogs & derivatives Dose-Response Relationship, Drug Drug Administration Schedule Drug Resistance, Neoplasm Female Glioma/blood/drug therapy/enzymology Humans Lymphocytes/*enzymology Male Melanoma/blood/drug therapy/enzymology Middle Aged Nitrosourea Compounds/administration & dosage/adverse effects O(6)-Methylguanine-DNA Methyltransferase/*blood Organophosphorus Compounds/administration & dosage/adverse effects
Pubmed
Web of science
Open Access
Yes
Create date
28/01/2008 8:31
Last modification date
25/09/2019 6:09
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