RT Journal Article
SR Electronic
T1 Prolonged Inhibition of<em>O</em>
<sup>6</sup>-Methylguanine DNA Methyltransferase in Human Tumor Cells by <em>O</em>
<sup>6</sup>-Benzylguanine In Vitro and In Vivo
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1269
OP 1275
VO 291
IS 3
A1 Kreklau, Emiko L.
A1 Kurpad, Chandrika
A1 Williams, David A.
A1 Erickson, Leonard C.
YR 1999
UL http://jpet.aspetjournals.org/content/291/3/1269.abstract
AB 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), &gt;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 &gt;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. The American Society for Pharmacology and Experimental Therapeutics