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

Emiko L. Kreklau, Naili Liu, Zhaohua Li, Kenneth Cornetta, Leonard C. Erickson

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Abstract

Previous studies have demonstrated that optimal reversal of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance requires complete inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) for at least 24 h following BCNU administration. In preparation for clinical trials at this institution, this study was undertaken to compare the efficacy of a conventional single-bolus dose versus double-bolus dose treatments with O6-benzylguanine (BG) in depleting MGMT activity in vivo. In xenograft human glioma SF767 tumors, a single 30-mg/kg bolus dose of BG completely inhibited MGMT activity for at least 8 h, but approximately 50% of the basal MGMT activity recovered within 24 h. To sustain the MGMT depletion for 24 h, a second bolus injection of BG at escalating doses was administered 8 h after the first dose. Second bolus doses of 5, 10, and 15 mg/kg BG attenuated the MGMT recovery in a dose-dependent manner compared with the single 30-mg/kg BG dose alone. When the 15-mg/kg BG dose was administered 8 h after the 30-mg/kg initial dose, MGMT activity was completely inactivated in the tumor xenografts for 24 h. This double-bolus BG treatment also depleted MGMT activity in normal murine tissues, including the liver, kidney, lung, brain, spleen, and bone marrow; and the kinetics of MGMT recovery varied among these tissues. When combined with BCNU treatment, the double-bolus BG treatment would be expected to produce greater antitumor activity in future trials than the conventional single-bolus BG treatment.

Original languageEnglish
Pages (from-to)524-530
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume297
Issue number2
StatePublished - 2001

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Methyltransferases
Oligonucleotides
Carmustine
DNA
Therapeutics
Heterografts
O-(6)-methylguanine
O(6)-benzylguanine
Glioma
DNA Repair
Neoplasms
Spleen
Bone Marrow
Clinical Trials
Kidney
Lung
Injections
Liver
Brain

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "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",
abstract = "Previous studies have demonstrated that optimal reversal of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance requires complete inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) for at least 24 h following BCNU administration. In preparation for clinical trials at this institution, this study was undertaken to compare the efficacy of a conventional single-bolus dose versus double-bolus dose treatments with O6-benzylguanine (BG) in depleting MGMT activity in vivo. In xenograft human glioma SF767 tumors, a single 30-mg/kg bolus dose of BG completely inhibited MGMT activity for at least 8 h, but approximately 50{\%} of the basal MGMT activity recovered within 24 h. To sustain the MGMT depletion for 24 h, a second bolus injection of BG at escalating doses was administered 8 h after the first dose. Second bolus doses of 5, 10, and 15 mg/kg BG attenuated the MGMT recovery in a dose-dependent manner compared with the single 30-mg/kg BG dose alone. When the 15-mg/kg BG dose was administered 8 h after the 30-mg/kg initial dose, MGMT activity was completely inactivated in the tumor xenografts for 24 h. This double-bolus BG treatment also depleted MGMT activity in normal murine tissues, including the liver, kidney, lung, brain, spleen, and bone marrow; and the kinetics of MGMT recovery varied among these tissues. When combined with BCNU treatment, the double-bolus BG treatment would be expected to produce greater antitumor activity in future trials than the conventional single-bolus BG treatment.",
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AU - Liu, Naili

AU - Li, Zhaohua

AU - Cornetta, Kenneth

AU - Erickson, Leonard C.

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