PT - JOURNAL ARTICLE AU - Stefania D'Atri AU - Grazia Graziani AU - Pedro Miguel Lacal AU - Vittoria Nisticò AU - Sara Gilberti AU - Isabella Faraoni AU - Amanda J. Watson AU - Enzo Bonmassar AU - Geoffrey P. Margison TI - Attenuation of <em>O</em> <sup>6</sup>-Methylguanine-DNA Methyltransferase Activity and mRNA Levels by Cisplatin and Temozolomide in Jurkat Cells DP - 2000 Aug 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 664--671 VI - 294 IP - 2 4099 - http://jpet.aspetjournals.org/content/294/2/664.short 4100 - http://jpet.aspetjournals.org/content/294/2/664.full SO - J Pharmacol Exp Ther2000 Aug 01; 294 AB - The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is important in cellular resistance to certain alkylating antitumor agents such as the methylating drug temozolomide (TMZ). To provide a more rational basis for clinical combinations with another commonly used drug, cisplatin, we assessed the modulation of MGMT protein and mRNA levels in the human leukemic cell line Jurkat after treatment with these agents. Cisplatin decreased MGMT activity in a time- and dose-dependent manner, with maximal suppression (50%) observed 24 h after treatment with 25 μM cisplatin. This was probably the result of decreased transcription of the MGMT gene, because there was an earlier nadir of MGMT mRNA levels after cisplatin treatment and neither cisplatin nor DNA reacted with cisplatin in vitro was able to inhibit MGMT activity in an in vitro assay. TMZ alone depleted MGMT activity in a time- and dose-dependent manner with almost complete loss of activity occurring immediately after treatment with 500 μM TMZ. Combinations of cisplatin (12.5 μM) and TMZ (250 μM) caused substantial and prolonged MGMT depletion with recovery to only 30% of pretreatment levels by 48 h. These results suggest that the clinical efficacy of TMZ and cisplatin may be improved by appropriate schedules of combinations of these agents. The American Society for Pharmacology and Experimental Therapeutics