|
|
Sequential administration of temozolomide and
fotemustine: depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes
and in tumours
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.
Centre
Pluridisciplinaire d'Oncologie, Lausanne, Switzerland
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.
PMID: 10470431 [PubMed - indexed for
MEDLINE]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10470431&dopt=Abstract
|
