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

M. Gander, S. Leyvraz, L. Decosterd, M. Bonfanti, C. Marzolini, F. Shen, D. Liénard, L. Perey, G. Colella, J. Biollaz, F. Lejeune, D. Yarosh, M. Belanich, M. D'Incalci

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 close (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 turnout for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.

Original languageEnglish (US)
Pages (from-to)831-838
Number of pages8
JournalAnnals of Oncology
Volume10
Issue number7
DOIs
StatePublished - 1999
Externally publishedYes

Fingerprint

temozolomide
fotemustine
Guanine
Transferases
Lymphocytes
DNA
Blood Cells
Neoplasms
Melanoma
Pharmacokinetics
Dacarbazine
Glioma
DNA Repair
Area Under Curve

Keywords

  • Melanoma
  • Pharmacodynamics
  • Pharmacokinetics
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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.; Liénard, D.; Perey, L.; Colella, G.; Biollaz, J.; Lejeune, F.; Yarosh, D.; Belanich, M.; D'Incalci, M.

In: Annals of Oncology, Vol. 10, No. 7, 1999, p. 831-838.

Research output: Contribution to journalArticle

Gander, M, Leyvraz, S, Decosterd, L, Bonfanti, M, Marzolini, C, Shen, F, Liénard, D, Perey, L, Colella, G, Biollaz, J, Lejeune, F, Yarosh, D, Belanich, M & D'Incalci, M 1999, 'Sequential administration of temozolomide and fotemustine: Depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours', Annals of Oncology, vol. 10, no. 7, pp. 831-838. https://doi.org/10.1023/A:1008304032421
Gander, M. ; Leyvraz, S. ; Decosterd, L. ; Bonfanti, M. ; Marzolini, C. ; Shen, F. ; Liénard, D. ; Perey, L. ; Colella, G. ; Biollaz, J. ; Lejeune, F. ; Yarosh, D. ; Belanich, M. ; D'Incalci, M. / Sequential administration of temozolomide and fotemustine : Depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours. In: Annals of Oncology. 1999 ; Vol. 10, No. 7. pp. 831-838.
@article{ddc52546f79f462a8faeda8a95e47bb5,
title = "Sequential administration of temozolomide and fotemustine: Depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours",
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 close (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 turnout for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.",
keywords = "Melanoma, Pharmacodynamics, Pharmacokinetics, Temozolomide",
author = "M. Gander and S. Leyvraz and L. Decosterd and M. Bonfanti and C. Marzolini and F. Shen and D. Li{\'e}nard and L. Perey and G. Colella and J. Biollaz and F. Lejeune and D. Yarosh and M. Belanich and M. D'Incalci",
year = "1999",
doi = "10.1023/A:1008304032421",
language = "English (US)",
volume = "10",
pages = "831--838",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "7",

}

TY - JOUR

T1 - Sequential administration of temozolomide and fotemustine

T2 - Depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours

AU - Gander, M.

AU - Leyvraz, S.

AU - Decosterd, L.

AU - Bonfanti, M.

AU - Marzolini, C.

AU - Shen, F.

AU - Liénard, D.

AU - Perey, L.

AU - Colella, G.

AU - Biollaz, J.

AU - Lejeune, F.

AU - Yarosh, D.

AU - Belanich, M.

AU - D'Incalci, M.

PY - 1999

Y1 - 1999

N2 - 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 close (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 turnout for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.

AB - 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 close (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 turnout for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.

KW - Melanoma

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Temozolomide

UR - http://www.scopus.com/inward/record.url?scp=0032793312&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032793312&partnerID=8YFLogxK

U2 - 10.1023/A:1008304032421

DO - 10.1023/A:1008304032421

M3 - Article

C2 - 10470431

AN - SCOPUS:0032793312

VL - 10

SP - 831

EP - 838

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 7

ER -