Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules

A. W. Tolcher, S. L. Gerson, L. Denis, C. Geyer, L. A. Hammond, A. Patnaik, A. D. Goetz, G. Schwartz, T. Edwards, L. Reyderman, P. Statkevich, D. L. Cutler, E. K. Rowinsky

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Abstract

Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGAT), has demonstrated anticancer activity on protracted schedules. Protracted schedules may lead to an 'autoenhancement' of temozolomide's inherent cytotoxic potential by cumulative reduction of the cell's capacity for AGAT-mediated DNA repair and resistance. This study was undertaken to characterise AGAT inactivation and regeneration in the peripheral blood mononuclear cells (PBMCs) of patients treated on two protracted temozolomide schedules, O6-alkyl guanine-DNA alkyltransferase activity was measured in the PBMCs of patients treated on two phase I protracted temozolomide studies. Patients were treated daily for either 7 days every 2 weeks (Schedule A) or 21 days every 4 weeks (Schedule B). The effects of various temozolomide doses (75-175 mg m-2), treatment duration (7-21 days), and temozolomide plasma levels on AGAT inactivation and regeneration, as well as the relation between AGAT inactivation and toxicity, were studied. O6-alkyl guanine-DNA alkyltransferase activity in PBMCs was measured serially in 52 patients. Marked inactivation of AGAT occurred following 7 days of temozolomide treatment, with mean AGAT activity decreasing by 72% (P < 0.0001). Similarly, mean AGAT activity decreased by 63 and 73% after 14 and 21 days of treatment, respectively (P < 0.001 for both comparisons). O6-alkyl guanine-DNA alkyltransferase inactivation was greater after 7 days of treatment with higher doses of temozolomide than lower doses and remained markedly reduced 7 days post-treatment. However, AGAT inactivation following temozolomide treatment for 14 and 21 days was similar at all doses. On the continuous 21-day schedule, AGAT inactivation was significantly greater in patients who experienced severe thrombocytopenia than those who did not (90.3±5.5 vs 72.5 ± 16.1%, P < 0.045). In Conclusion, protracted administration of temozolomide, even at relatively low daily doses, leads to significant and prolonged depletion of AGAT activity, which may enhance the antitumour activity of the agent.

Original languageEnglish (US)
Pages (from-to)1004-1011
Number of pages8
JournalBritish Journal of Cancer
Volume88
Issue number7
DOIs
StatePublished - Apr 7 2003

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temozolomide
Appointments and Schedules
Guanine
Blood Cells
DNA alkyltransferase
Regeneration
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tolcher, A. W., Gerson, S. L., Denis, L., Geyer, C., Hammond, L. A., Patnaik, A., ... Rowinsky, E. K. (2003). Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. British Journal of Cancer, 88(7), 1004-1011. https://doi.org/10.1038/sj.bjc.6600827

Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. / Tolcher, A. W.; Gerson, S. L.; Denis, L.; Geyer, C.; Hammond, L. A.; Patnaik, A.; Goetz, A. D.; Schwartz, G.; Edwards, T.; Reyderman, L.; Statkevich, P.; Cutler, D. L.; Rowinsky, E. K.

In: British Journal of Cancer, Vol. 88, No. 7, 07.04.2003, p. 1004-1011.

Research output: Contribution to journalArticle

Tolcher, AW, Gerson, SL, Denis, L, Geyer, C, Hammond, LA, Patnaik, A, Goetz, AD, Schwartz, G, Edwards, T, Reyderman, L, Statkevich, P, Cutler, DL & Rowinsky, EK 2003, 'Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules', British Journal of Cancer, vol. 88, no. 7, pp. 1004-1011. https://doi.org/10.1038/sj.bjc.6600827
Tolcher, A. W. ; Gerson, S. L. ; Denis, L. ; Geyer, C. ; Hammond, L. A. ; Patnaik, A. ; Goetz, A. D. ; Schwartz, G. ; Edwards, T. ; Reyderman, L. ; Statkevich, P. ; Cutler, D. L. ; Rowinsky, E. K. / Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. In: British Journal of Cancer. 2003 ; Vol. 88, No. 7. pp. 1004-1011.
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abstract = "Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGAT), has demonstrated anticancer activity on protracted schedules. Protracted schedules may lead to an 'autoenhancement' of temozolomide's inherent cytotoxic potential by cumulative reduction of the cell's capacity for AGAT-mediated DNA repair and resistance. This study was undertaken to characterise AGAT inactivation and regeneration in the peripheral blood mononuclear cells (PBMCs) of patients treated on two protracted temozolomide schedules, O6-alkyl guanine-DNA alkyltransferase activity was measured in the PBMCs of patients treated on two phase I protracted temozolomide studies. Patients were treated daily for either 7 days every 2 weeks (Schedule A) or 21 days every 4 weeks (Schedule B). The effects of various temozolomide doses (75-175 mg m-2), treatment duration (7-21 days), and temozolomide plasma levels on AGAT inactivation and regeneration, as well as the relation between AGAT inactivation and toxicity, were studied. O6-alkyl guanine-DNA alkyltransferase activity in PBMCs was measured serially in 52 patients. Marked inactivation of AGAT occurred following 7 days of temozolomide treatment, with mean AGAT activity decreasing by 72{\%} (P < 0.0001). Similarly, mean AGAT activity decreased by 63 and 73{\%} after 14 and 21 days of treatment, respectively (P < 0.001 for both comparisons). O6-alkyl guanine-DNA alkyltransferase inactivation was greater after 7 days of treatment with higher doses of temozolomide than lower doses and remained markedly reduced 7 days post-treatment. However, AGAT inactivation following temozolomide treatment for 14 and 21 days was similar at all doses. On the continuous 21-day schedule, AGAT inactivation was significantly greater in patients who experienced severe thrombocytopenia than those who did not (90.3±5.5 vs 72.5 ± 16.1{\%}, P < 0.045). In Conclusion, protracted administration of temozolomide, even at relatively low daily doses, leads to significant and prolonged depletion of AGAT activity, which may enhance the antitumour activity of the agent.",
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