JPET Assistant Professor of Medicine (Clinician-Educator)

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kreklau, E. L.
Right arrow Articles by Erickson, L. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kreklau, E. L.
Right arrow Articles by Erickson, L. C.

Vol. 291, Issue 3, 1269-1275, December 1999

Prolonged Inhibition of O6-Methylguanine DNA Methyltransferase in Human Tumor Cells by O6-Benzylguanine In Vitro and In Vivo1

Emiko L. Kreklau, Chandrika Kurpad, David A. Williams and Leonard C. Erickson

Indiana University Cancer Center, Department of Pharmacology and Toxicology, Section of Pediatric Hematology/Oncology Herman B Wells Center for Pediatric Research (E.L.K., C.K., L.C.E.), Department of Pediatrics (D.A.W.), and Howard Hughes Medical Institute (D.A.W.), Indiana University School of Medicine, Indianapolis, Indiana

We previously demonstrated that sustained depletion of methylguanine DNA methyltransferase (MGMT) activity is required for optimal reversal of chloroethylnitrosourea resistance in tumor cells. The purpose of this study was to design O6-benzylguanine (BG) treatments that deplete MGMT activity in tumor cells and xenograft tumors in a prolonged manner. When SF767 cells were treated with a bolus dose of BG (25 µM for 1 h), >95% of MGMT activity was depleted but 33% of the activity recovered within 24 h. In contrast, MGMT activity was completely depleted for 24 h when cells were pretreated with a low dose of BG (2.5 µM) for 24 h, followed by the bolus dose and same low-dose treatment for 24 h. This combination regimen of pre- and post-treatments with a bolus dose sensitized cells N,N'-bis(2-chloroethyl)-N-nitrosourea in vitro by ~2-fold more than the bolus dose alone. Similar BG treatment with Alzet micro-osmotic pumps produced sustained inhibition of MGMT activity in vivo. In xenograft SF767 tumors, low-dose pre- and post-treatments (8 mg/kg over 24 h) combined with an i.p. bolus dose (80 mg/kg) of BG inhibited >95% of MGMT activity for 24 h after the bolus. The bolus dose alone did not deplete MGMT for 24 h. These results demonstrate that combination low-dose and bolus BG treatment is superior to the bolus dose alone in depleting MGMT activity in a sustained manner in vitro and in vivo. When combined with N,N'-bis(2-chloroethyl)-N-nitrosourea treatment, this BG regimen also should also produce greater antitumor activity than the single bolus dose evaluated clinically.

0022-3565/99/2913-1269$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
S. Kesari, D. Schiff, J. Drappatz, D. LaFrankie, L. Doherty, E. A. Macklin, A. Muzikansky, S. Santagata, K. L. Ligon, A. D. Norden, et al.
Phase II Study of Protracted Daily Temozolomide for Low-Grade Gliomas in Adults
Clin. Cancer Res., January 1, 2009; 15(1): 330 - 337.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. M. Wagner, R. E. McLendon, K. J. Yoon, B. D. Weiss, C. A. Billups, and M. K. Danks
Targeting Methylguanine-DNA Methyltransferase in the Treatment of Neuroblastoma
Clin. Cancer Res., September 15, 2007; 13(18): 5418 - 5425.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
T. Ueno, S. H. Ko, E. Grubbs, Y. Yoshimoto, C. Augustine, Z. Abdel-Wahab, T.-Y. Cheng, O. I. Abdel-Wahab, S. K. Pruitt, H. S. Friedman, et al.
Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine.
Mol. Cancer Ther., March 1, 2006; 5(3): 732 - 738.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. S. Bobola, J. R. Silber, R. G. Ellenbogen, J. R. Geyer, A. Blank, and R. D. Goff
O6-Methylguanine-DNA Methyltransferase, O6-Benzylguanine, and Resistance to Clinical Alkylators in Pediatric Primary Brain Tumor Cell Lines
Clin. Cancer Res., April 1, 2005; 11(7): 2747 - 2755.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
Q. Zhang, D. W. Ohannesian, and L. C. Erickson
Hammerhead Ribozyme-Mediated Sensitization of Human Tumor Cells after Treatment with 1,3-Bis(2-chloroethyl)-1-nitrosourea
J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 506 - 514.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
E. L. Kreklau, K. E. Pollok, B. J. Bailey, N. Liu, J. R. Hartwell, D. A. Williams, and L. C. Erickson
Hematopoietic expression of O6-methylguanine DNA methyltransferase-P140K allows intensive treatment of human glioma xenografts with combination O6-benzylguanine and 1,3-bis-(2-chloroethyl)-1-nitrosourea
Mol. Cancer Ther., December 1, 2003; 2(12): 1321 - 1329.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. R. Silber, M. S. Bobola, A. Blank, K. D. Schoeler, P. D. Haroldson, M. B. Huynh, and D. D. Kolstoe
The Apurinic/Apyrimidinic Endonuclease Activity of Ape1/Ref-1 Contributes to Human Glioma Cell Resistance to Alkylating Agents and Is Elevated by Oxidative Stress
Clin. Cancer Res., September 1, 2002; 8(9): 3008 - 3018.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
S. L. Gerson
Clinical Relevance of MGMT in the Treatment of Cancer
J. Clin. Oncol., May 1, 2002; 20(9): 2388 - 2399.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
Q. Zhang, D. W. Ohannesian, E. L. Kreklau, and L. C. Erickson
Modulation of 1,3-Bis-(2-chloroethyl)-1-nitrosourea Resistance in Human Tumor Cells Using Hammerhead Ribozymes Designed to Degrade O6-Methylguanine DNA Methyltransferase mRNA
J. Pharmacol. Exp. Ther., July 1, 2001; 298(1): 141 - 147.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
E. L. Kreklau, N. Liu, Z. Li, K. Cornetta, and L. C. Erickson
Comparison of Single- Versus Double-Bolus Treatments of O6-Benzylguanine for Depletion of O6-Methylguanine DNA Methyltransferase (MGMT) Activity in Vivo: Development of a Novel Fluorometric Oligonucleotide Assay for Measurement of Mgmt Activity
J. Pharmacol. Exp. Ther., April 12, 2001; 297(2): 524 - 530.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
A. E. Pegg, K. Goodtzova, N. A. Loktionova, S. Kanugula, G. T. Pauly, and R. C. Moschel
Inactivation of Human O6-Alkylguanine-DNA Alkyltransferase by Modified Oligodeoxyribonucleotides Containing O6-Benzylguanine
J. Pharmacol. Exp. Ther., March 1, 2001; 296(3): 958 - 965.
[Abstract] [Full Text]

Home page
 Clin. Cancer Res.Home page
D. M. Kokkinakis, D. B. Bocangel, S. C. Schold, R. C. Moschel, and A. E. Pegg
Thresholds of O6-Alkylguanine-DNA Alkyltransferase which Confer Significant Resistance of Human Glial Tumor Xenografts to Treatment with 1,3-Bis(2-chloroethyl)-1-nitrosourea or Temozolomide
Clin. Cancer Res., February 1, 2001; 7(2): 421 - 428.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics.