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O6-Benzylguanine
suppression of O6-alkylguanine-DNA alkyltransferase in
anaplastic gliomas
S. Clifford Schold Jr., Demetrius M. Kokkinakis, Susan M. Chang, Mitchel
S. Berger, Kenneth R. Hess, David Schiff, H. Ian Robins, Minesh P. Mehta, Karen
L. Fink, R.L. Davis, and Michael D. Prados
University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232
(S.C.S); Departments of Neurological Surgery (D.M.K.) and Neurology (K.L.F.),
The University of Texas Southwestern Medical Center, Dallas, TX 75390;
Departments of Neurological Surgery (S.M.C., M.S.B., M.D.P.) and Pathology
(R.L.D.), University of California at San Francisco, San Francisco, CA 94143;
Department of Biostatistics, The University of Texas M.D. Anderson Cancer
Center, Houston, TX 77030 (K.R.H.); Division of Neuro-Oncology, University of
Virginia, Charlottesville, VA 22908 (D.S.); Department of Medicine, Medical
Oncology Section, University of Wisconsin, Madison, WI 53792 (H.I.R.);
Department of Human Oncology, University of Wisconsin Medical School, Madison,
WI 53792 (M.P.M.); USA
The purpose of the study was to determine the dose of O6-benzylguanine
(BG) that would suppress O6-alkylguanine-DNA alkyltransferase
(AGT) activity to undetectable levels in > 90% of anaplastic gliomas, as
measured 6 h after a 1-h BG infusion.
Subjects who were scheduled for surgical resection of a known or presumed
anaplastic glioma received a 1-h infusion of BG.
Tumor tissue was surgically removed approximately 6 h after the end of the
infusion and was analyzed for AGT activity.
The BG dose was escalated until at least 11 of 14 subjects had no detectable AGT
activity.
An additional cohort of patients received the identified effective dose of BG
approximately 18 h before tumor resection in order to compare our results with
an earlier study using the longer time interval.
In the 79 subjects who were enrolled, there was no significant toxicity that was
attributed to the BG.
A dose-response relationship was determined between the BG dose and the
percentage of subjects with undetectable AGT.
A dose of 120 mg/m2 suppressed AGT to less than detectable levels in
17 of 18 patients when the drug-resection interval was 6 h.
With an 18-h interval, only 5 of 11 subjects had undetectable AGT at the
120-mg/m2 dose.
We conclude that a BG dose of 120 mg/m2 given 6 h before an
alkylating drug would be effective in suppressing AGT and possibly potentiating
the cytotoxic effects of the drug.
© 2003 Duke University Press
Source: http://juno.ingentaselect.com/cgi-bin/linker?ini=dup_no&reqidx=/cw/dup/15228517/v6n1/s5/p28
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