Limits...
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.

Show MeSH

Related in: MedlinePlus

Scatterplots of the percentage values of PBMC AGAT inactivation for Schedules A (day 8 values) and B (day 15 and 22 values) at each temozolomide dose: (A) 75 mg m−2 day−1 (day 8 only) and 85 mg m−2 day−1 (days 15 and 22); (B) 100 mg m−2 day−1; (C) 125 mg m−2 day−1; (D) 150 mg m−2 day−1; and (E) 175 mg m−2 day−1. Dose-limiting toxicity precluded daily treatment with temozolomide for longer than 7 days at the 150 and 175 mg m−2 day−1 dose levels.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2376384&req=5

fig2: Scatterplots of the percentage values of PBMC AGAT inactivation for Schedules A (day 8 values) and B (day 15 and 22 values) at each temozolomide dose: (A) 75 mg m−2 day−1 (day 8 only) and 85 mg m−2 day−1 (days 15 and 22); (B) 100 mg m−2 day−1; (C) 125 mg m−2 day−1; (D) 150 mg m−2 day−1; and (E) 175 mg m−2 day−1. Dose-limiting toxicity precluded daily treatment with temozolomide for longer than 7 days at the 150 and 175 mg m−2 day−1 dose levels.

Mentions: After 7 days of daily temozolomide treatment, the percentage decrements in AGAT activity were generally greater at the higher dose levels (125, 150, and 175 mg m−2 day−1) than at the lower dose levels (75 and 100 mg m−2 day−1), although the small number of patients treated at the lowest dose level were insufficient to provide statistical analysis of the dose-dependence of AGAT inactivation. The percentage decrements in AGAT activity averaged 51±0, 48±5, 81±13, 80±14, and 76±16% following 7 days of treatment with temozolomide doses of 75, 100, 125, 150, and 175 mg m−2 day−1, respectively. With more protracted temozolomide treatment (14 and 21 days), dose-related effects were no longer apparent and AGAT inactivation was similar at all dose levels. Furthermore, AGAT inactivation following 14 and 21 days of treatment with low doses temozolomide (85 and 100 mg m−2 day−1) was comparable to that achieved with higher doses (125, 150, and 175 mg m−2 day−1) administered for 7 days (Figure 2A–EFigure 2


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 the percentage values of PBMC AGAT inactivation for Schedules A (day 8 values) and B (day 15 and 22 values) at each temozolomide dose: (A) 75 mg m−2 day−1 (day 8 only) and 85 mg m−2 day−1 (days 15 and 22); (B) 100 mg m−2 day−1; (C) 125 mg m−2 day−1; (D) 150 mg m−2 day−1; and (E) 175 mg m−2 day−1. Dose-limiting toxicity precluded daily treatment with temozolomide for longer than 7 days at the 150 and 175 mg m−2 day−1 dose levels.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Scatterplots of the percentage values of PBMC AGAT inactivation for Schedules A (day 8 values) and B (day 15 and 22 values) at each temozolomide dose: (A) 75 mg m−2 day−1 (day 8 only) and 85 mg m−2 day−1 (days 15 and 22); (B) 100 mg m−2 day−1; (C) 125 mg m−2 day−1; (D) 150 mg m−2 day−1; and (E) 175 mg m−2 day−1. Dose-limiting toxicity precluded daily treatment with temozolomide for longer than 7 days at the 150 and 175 mg m−2 day−1 dose levels.
Mentions: After 7 days of daily temozolomide treatment, the percentage decrements in AGAT activity were generally greater at the higher dose levels (125, 150, and 175 mg m−2 day−1) than at the lower dose levels (75 and 100 mg m−2 day−1), although the small number of patients treated at the lowest dose level were insufficient to provide statistical analysis of the dose-dependence of AGAT inactivation. The percentage decrements in AGAT activity averaged 51±0, 48±5, 81±13, 80±14, and 76±16% following 7 days of treatment with temozolomide doses of 75, 100, 125, 150, and 175 mg m−2 day−1, respectively. With more protracted temozolomide treatment (14 and 21 days), dose-related effects were no longer apparent and AGAT inactivation was similar at all dose levels. Furthermore, AGAT inactivation following 14 and 21 days of treatment with low doses temozolomide (85 and 100 mg m−2 day−1) was comparable to that achieved with higher doses (125, 150, and 175 mg m−2 day−1) administered for 7 days (Figure 2A–EFigure 2

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