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Research ArticleArticle

Prolonged Inhibition ofO 6-Methylguanine DNA Methyltransferase in Human Tumor Cells by O 6-Benzylguanine In Vitro and In Vivo

Emiko L. Kreklau, Chandrika Kurpad, David A. Williams and Leonard C. Erickson
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1269-1275;
Emiko L. Kreklau
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Chandrika Kurpad
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David A. Williams
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Leonard C. Erickson
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Abstract

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 cellsN,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 withN,N′-bis(2-chloroethyl)-N-nitrosourea treatment, this BG regimen also should also produce greater antitumor activity than the single bolus dose evaluated clinically.

Footnotes

  • Send reprint requests to: Dr. Leonard C. Erickson, Indiana University Cancer Center, 1044 W. Walnut St., Bldg. R4, Rm. 168, Indianapolis, IN 46268. E-mail: lcericks{at}iupui.edu

  • ↵1 This research was supported by National Cancer Institute Grants CA 75426 (to D.A.W.) and CA 45628 (to L.C.E.).

  • Abbreviations:
    CENU
    chloroethylnitrosourea
    MGMT
    methylguanine DNA methyltransferase
    STZ
    streptozotocin
    BCNU
    N,N′-bis(2-chloroethyl)-N-nitrosourea
    MG
    O6-methylguanine
    BG
    O6-benzylguanine
    NOD/SCID
    naturally obese diabetic mice with severe combined immunodeficiency
    • Received June 10, 1999.
    • Accepted August 24, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Prolonged Inhibition ofO 6-Methylguanine DNA Methyltransferase in Human Tumor Cells by O 6-Benzylguanine In Vitro and In Vivo

Emiko L. Kreklau, Chandrika Kurpad, David A. Williams and Leonard C. Erickson
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1269-1275;

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Research ArticleArticle

Prolonged Inhibition ofO 6-Methylguanine DNA Methyltransferase in Human Tumor Cells by O 6-Benzylguanine In Vitro and In Vivo

Emiko L. Kreklau, Chandrika Kurpad, David A. Williams and Leonard C. Erickson
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1269-1275;
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