Annals of Oncology 10:831-838, 1999
© 1999 European Society for Medical Oncology
research-article |
Sequential administration of temozolomide and fotemustine: Depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours
lCemre Pluridisciplinaire d'Oncologie Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland
2Division de Pharmacologie Clinique, Département de Medecine, Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland
3Istituto di Ricerche Farmacologiche Mario Negri Milano, Italy
4Applied Genetics Inc. Freeport, NY, USA
Correspondence to: Centre Pluridisciplinaire d'Oncologie, CHUV BH 10, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland, E-mail: Serge. Leyvraz{at}chuv.hospvd.ch
Background: The DNA repair protein O6-alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitro-soureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloro-ethylnitrosoureas. 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.
melanoma, pharmacodynamics, pharmacokinetics, temozolomide
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