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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Attenuation of O 6-Methylguanine-DNA Methyltransferase Activity and mRNA Levels by Cisplatin and Temozolomide in Jurkat Cells

Stefania D'Atri, Grazia Graziani, Pedro Miguel Lacal, Vittoria Nisticò, Sara Gilberti, Isabella Faraoni, Amanda J. Watson, Enzo Bonmassar and Geoffrey P. Margison
Journal of Pharmacology and Experimental Therapeutics August 2000, 294 (2) 664-671;
Stefania D'Atri
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Grazia Graziani
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Pedro Miguel Lacal
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Vittoria Nisticò
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Sara Gilberti
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Isabella Faraoni
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Amanda J. Watson
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Enzo Bonmassar
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Geoffrey P. Margison
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. Stefania D'Atri, Laboratory of Pharmacology, Istituto Dermopatico Dell'Immacolata (IDI-IRCCS), Via dei Monti di Creta 104, 00167 Rome, Italy. E-mail: s.datri{at}idi.it

  • ↵1 This study was supported by a grant from the Italian Ministry of Health. Work at the Paterson Institute was supported by the Cancer Research Campaign.

  • Abbreviations:
    O6-G
    O6-guanine
    BCNU
    1,3-bis(2-chloroethyl)-1-nitrosourea
    CM
    complete medium
    DTIC
    5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    MTIC
    5-(3-methyl-1-triazeno)imidazole-4-carboxamide
    MGMT
    O6-methylguanine-DNA methyltransferase
    rhMGMT
    recombinant humanO6-methylguanine-DNA methyltransferase
    MMR
    mismatch repair
    O6-BeG
    O6-benzylguanine
    O6-MeG
    O6-methylguanine
    TE
    Tris-HCl/EDTA
    PTT
    paired Student's t test
    TMZ
    temozolomide [8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one]
    • Received January 18, 2000.
    • Accepted May 2, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 2
1 Aug 2000
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Attenuation of O 6-Methylguanine-DNA Methyltransferase Activity and mRNA Levels by Cisplatin and Temozolomide in Jurkat Cells

Stefania D'Atri, Grazia Graziani, Pedro Miguel Lacal, Vittoria Nisticò, Sara Gilberti, Isabella Faraoni, Amanda J. Watson, Enzo Bonmassar and Geoffrey P. Margison
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 664-671;

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Attenuation of O 6-Methylguanine-DNA Methyltransferase Activity and mRNA Levels by Cisplatin and Temozolomide in Jurkat Cells

Stefania D'Atri, Grazia Graziani, Pedro Miguel Lacal, Vittoria Nisticò, Sara Gilberti, Isabella Faraoni, Amanda J. Watson, Enzo Bonmassar and Geoffrey P. Margison
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 664-671;
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