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

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Br J Cancer. 2003 Apr 7;88(7):1004-11.
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.Institute of Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA.

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.