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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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(A) Scatterplot of the percentage values of PBMC AGAT inactivation as a function of the total cumulative temozolomide dose administered up to the time of PBMC sampling (R2=0.102). (B) Scatterplot of temozolomide exposure as the product of AUC0-t multiplied by total days temozolomide administered prior to PBMC sampling (R2=0.188).
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fig3: (A) Scatterplot of the percentage values of PBMC AGAT inactivation as a function of the total cumulative temozolomide dose administered up to the time of PBMC sampling (R2=0.102). (B) Scatterplot of temozolomide exposure as the product of AUC0-t multiplied by total days temozolomide administered prior to PBMC sampling (R2=0.188).

Mentions: Since both dose and duration of temozolomide treatment appeared to be related to AGAT inactivation, relations between AGAT inactivation and both total temozolomide dose and AUC0−t were sought. A scatterplot of the percentage decrements in AGAT activity in all PBMC samples as a function of the total temozolomide dose (in mg) and plasma AUC administered up to the time of PBMC sampling is displayed in Figure 3Figure 3


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)

(A) Scatterplot of the percentage values of PBMC AGAT inactivation as a function of the total cumulative temozolomide dose administered up to the time of PBMC sampling (R2=0.102). (B) Scatterplot of temozolomide exposure as the product of AUC0-t multiplied by total days temozolomide administered prior to PBMC sampling (R2=0.188).
© Copyright Policy
Related In: Results  -  Collection

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

fig3: (A) Scatterplot of the percentage values of PBMC AGAT inactivation as a function of the total cumulative temozolomide dose administered up to the time of PBMC sampling (R2=0.102). (B) Scatterplot of temozolomide exposure as the product of AUC0-t multiplied by total days temozolomide administered prior to PBMC sampling (R2=0.188).
Mentions: Since both dose and duration of temozolomide treatment appeared to be related to AGAT inactivation, relations between AGAT inactivation and both total temozolomide dose and AUC0−t were sought. A scatterplot of the percentage decrements in AGAT activity in all PBMC samples as a function of the total temozolomide dose (in mg) and plasma AUC administered up to the time of PBMC sampling is displayed in Figure 3Figure 3

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