Attenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells.

2.50
Hdl Handle:
http://hdl.handle.net/10541/88614
Title:
Attenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells.
Authors:
D'Atri, Stefania; Graziani, Grazia; Lacal, Pedro M; Nisticò, Vittoria; Gilberti, Sara; Faraoni, Isabella; Watson, Amanda J; Bonmassar, Enzo; Margison, Geoffrey P
Abstract:
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.
Affiliation:
Istituto Dermopatico Dell'Immacolata, Rome, Italy. s.datri@idi.it
Citation:
Attenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells. 2000, 294 (2):664-71 J. Pharmacol. Exp. Ther.
Journal:
The Journal of Pharmacology and Experimental Therapeutics
Issue Date:
Aug-2000
URI:
http://hdl.handle.net/10541/88614
PubMed ID:
10900246
Type:
Article
Language:
en
ISSN:
0022-3565
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorD'Atri, Stefaniaen
dc.contributor.authorGraziani, Graziaen
dc.contributor.authorLacal, Pedro Men
dc.contributor.authorNisticò, Vittoriaen
dc.contributor.authorGilberti, Saraen
dc.contributor.authorFaraoni, Isabellaen
dc.contributor.authorWatson, Amanda Jen
dc.contributor.authorBonmassar, Enzoen
dc.contributor.authorMargison, Geoffrey Pen
dc.date.accessioned2009-12-29T10:19:42Z-
dc.date.available2009-12-29T10:19:42Z-
dc.date.issued2000-08-
dc.identifier.citationAttenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells. 2000, 294 (2):664-71 J. Pharmacol. Exp. Ther.en
dc.identifier.issn0022-3565-
dc.identifier.pmid10900246-
dc.identifier.urihttp://hdl.handle.net/10541/88614-
dc.description.abstractThe 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.en
dc.language.isoenen
dc.subjectCancer Drug Resistanceen
dc.subject.meshAntineoplastic Agents-
dc.subject.meshAntineoplastic Agents, Alkylating-
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols-
dc.subject.meshBase Pair Mismatch-
dc.subject.meshCisplatin-
dc.subject.meshDNA Repair-
dc.subject.meshDacarbazine-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshGene Expression-
dc.subject.meshHumans-
dc.subject.meshJurkat Cells-
dc.subject.meshKinetics-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshRNA, Messenger-
dc.titleAttenuation of O(6)-methylguanine-DNA methyltransferase activity and mRNA levels by cisplatin and temozolomide in jurkat cells.en
dc.typeArticleen
dc.contributor.departmentIstituto Dermopatico Dell'Immacolata, Rome, Italy. s.datri@idi.iten
dc.identifier.journalThe Journal of Pharmacology and Experimental Therapeuticsen

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