Attenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells.
Attenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells.
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Jurkat 细胞中顺铂和替莫唑胺减弱 O(6)-甲基鸟嘌呤-DNA 甲基转移酶活性和 mRNA 水平。
DOI：
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发表时间：
2000
影响因子：
3.5
通讯作者：
G. Margison
中科院分区：
文献类型：
--
作者：
S. D’Atri;G. Graziani;P. Lacal;V. Nisticò;S. Gilberti;I. Faraoni;A. Watson;E. Bonmassar;G. Margison
DNA修复蛋白O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）在细胞对某些烷基化抗肿瘤药物（如甲基化药物替莫唑胺（TMZ））的耐药性中起重要作用。为了给临床联合使用另一种常用药物顺铂提供更合理的依据，我们评估了这些药物治疗后人类白血病细胞系Jurkat中MGMT蛋白和mRNA水平的调节。顺铂以时间和剂量依赖的方式降低MGMT活性，在25微米顺铂治疗24小时后观察到最大抑制（50%）。这可能是MGMT基因转录减少的结果，因为顺铂治疗后MGMT mRNA水平较早降至最低点，并且在体外实验中，顺铂和DNA与顺铂的反应都不能抑制MGMT活性。单独TMZ以时间和剂量依赖的方式减少MGMT活性，在500微米TMZ治疗后几乎完全丧失活性。顺铂（12.5 microM）和顺铂（250 microM）联合使用可导致MGMT大量耗损，且时间较长，48小时后仅恢复到预处理水平的30%。这些结果表明，适当的联合使用时间表可提高TMZ和顺铂的临床疗效。
The DNA repair protein O(6)-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 microM 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 microM TMZ. Combinations of cisplatin (12.5 microM) and TMZ (250 microM) 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.
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影响因子：
11.2
作者：
Xu-Welliver,M;Leitão,J;Kanugula,S;Pegg,AE
通讯作者：
Pegg,AE
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影响因子：
11.2
作者：
Pieper,RO;Futscher,BW;Dong,Q;Erickson,LC
通讯作者：
Erickson,LC
人 O6-烷基鸟嘌呤-DNA 烷基转移酶中的单个氨基酸变化降低了对 O6-苄基鸟嘌呤失活的敏感性。
影响因子：
11.2
作者：
Crone,TM;Pegg,AE
通讯作者：
Pegg,AE
影响因子：
7.4
作者：
Rettori MM;de Carvalho AC;Longo AL;de Oliveira CZ;Kowalski LP;Carvalho AL;Vettore AL
通讯作者：
Vettore AL
使用链脲佐菌素调节 O6-烷基鸟嘌呤-DNA 烷基转移酶介导的卡莫司汀耐药性：I 期试验。
影响因子：
11.2
作者：
Panella,TJ;Smith,DC;Schold,SC;Rogers,MP;Winer,EP;Fine,RL;Crawford,J;Herndon2nd,JE;Trump,DL
通讯作者：
Trump,DL