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

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 - Br. J. Cancer (2003)

Bottom Line: O(6)-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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. atolcher@saci.org

ABSTRACT
Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O(6)-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. O(6)-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. O(6)-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). O(6)-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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Related in: MedlinePlus

Scatterplots of AGAT activity in PBMCs sampled (A), pretreatment and after 7 days of daily temozolomide treatment administered (at doses of 75–175 mg m−2 day−1) on Schedule A; and (B) after 14 and 21 days of temozolomide treatment (at doses of 85–125 mg m−2 day−1) on Schedule B.
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fig1: Scatterplots of AGAT activity in PBMCs sampled (A), pretreatment and after 7 days of daily temozolomide treatment administered (at doses of 75–175 mg m−2 day−1) on Schedule A; and (B) after 14 and 21 days of temozolomide treatment (at doses of 85–125 mg m−2 day−1) on Schedule B.

Mentions: Peripheral blood mononuclear cells were collected serially in 52 of the 72 patients enrolled in the two clinical studies. In all, 20 patients did not have samples collected; 10 who were entered into the clinical studies prior to the protocol amendment for AGAT analysis, and 10 patients who had inadequate samples for analysis. O6-alkylguanine-DNA alkyltransferase activity in PBMCs was measured serially in 25 and 27 patients treated with temozolomide on Schedules A and B, respectively. Scatterplots of all assessments of PBMC AGAT activity are displayed in Figure 1A, BFigure 1


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

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 - Br. J. Cancer (2003)

Scatterplots of AGAT activity in PBMCs sampled (A), pretreatment and after 7 days of daily temozolomide treatment administered (at doses of 75–175 mg m−2 day−1) on Schedule A; and (B) after 14 and 21 days of temozolomide treatment (at doses of 85–125 mg m−2 day−1) on Schedule B.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376384&req=5

fig1: Scatterplots of AGAT activity in PBMCs sampled (A), pretreatment and after 7 days of daily temozolomide treatment administered (at doses of 75–175 mg m−2 day−1) on Schedule A; and (B) after 14 and 21 days of temozolomide treatment (at doses of 85–125 mg m−2 day−1) on Schedule B.
Mentions: Peripheral blood mononuclear cells were collected serially in 52 of the 72 patients enrolled in the two clinical studies. In all, 20 patients did not have samples collected; 10 who were entered into the clinical studies prior to the protocol amendment for AGAT analysis, and 10 patients who had inadequate samples for analysis. O6-alkylguanine-DNA alkyltransferase activity in PBMCs was measured serially in 25 and 27 patients treated with temozolomide on Schedules A and B, respectively. Scatterplots of all assessments of PBMC AGAT activity are displayed in Figure 1A, BFigure 1

Bottom Line: O(6)-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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. atolcher@saci.org

ABSTRACT
Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O(6)-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. O(6)-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. O(6)-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). O(6)-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.

Show MeSH
Related in: MedlinePlus