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 proteinO 6-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 withO 6-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.
Footnotes
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Send reprint requests to: Dr. Leonard Erickson, Indiana University Cancer Center, 1044 W. Walnut St., Bldg. R4, Room 168, Indianapolis, IN 46202. E-mail: lcericks{at}iupui.edu
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This research was supported by National Cancer Institute Grants CA 75426 (to David A. Williams) and CA 45628 (to L.C.E.).
- Abbreviations:
- MGMT
- O 6-methylguanine DNA methyltransferase
- BCNU
- 1,3-bis(2-chloroethyl)-1-nitrosourea
- BG
- O 6-benzylguanine
- PEG-400
- polyethylene glycol 400
- NOD/SCID
- nonobese diabetic mice with severe combined immunodeficiency
- bp
- base pair
- HEX
- 5′-hexachloro-fluorescein phosphoramidite
- O6-MeG
- O 6-methylguanine
- Received October 10, 2000.
- Accepted January 5, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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