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Research ArticleArticle

Involvement of the Mismatch Repair System in Temozolomide-Induced Apoptosis

Stefania D’Atri, Lucio Tentori, Pedro Miguel Lacal, Grazia Graziani, Elena Pagani, Elena Benincasa, Giovanna Zambruno, Enzo Bonmassar and Josef Jiricny
Molecular Pharmacology August 1998, 54 (2) 334-341; DOI: https://doi.org/10.1124/mol.54.2.334
Stefania D’Atri
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Lucio Tentori
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Pedro Miguel Lacal
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Grazia Graziani
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Elena Pagani
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Elena Benincasa
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Giovanna Zambruno
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Enzo Bonmassar
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Abstract

Postreplicative mismatch repair plays a major role in mediating the cytotoxicity of agents generatingO 6-methylguanine in DNA. We previously showed that a methylating antitumor triazene compound, temozolomide, induces apoptosis and that the persistence ofO 6-methylguanine in DNA is required to trigger the process. We wanted to test whether the latter apoptotic signal is dependent on a functional mismatch repair system. To this end, we used two human lymphoblastoid cell lines (i.e., the mismatch repair-proficient TK6 line and its mismatch repair-deficient subline MT1) that are both deficient inO 6-methylguanine repair. Temozolomide treatment of TK6 cells brought about efficient cell growth inhibition, G2/M arrest, and apoptosis, as indicated by the results of cytofluorimetric analysis of 5-bromo-2′-deoxyuridine incorporation and DNA content and evaluation of DNA fragmentation. The drug treatment resulted also in the induction of p53 and p21/waf-1 protein expression. In contrast, MT1 cells were highly resistant to the drug and no p53 and p21/waf-1 induction was observed. Importantly, we could show that MT1 cells are not deficient in the p53-dependent apoptosis pathway; treatment with etoposide, a topoisomerase II inhibitor, resulted in p53 and p21/waf-1 protein expression and apoptosis in both cell lines. In conclusion, we demonstrate the existence of a link between a functional mismatch repair system and the trigger of apoptosis in cells exposed to clinically relevant concentrations of temozolomide. The results also suggest that p53 induction in response toO 6-guanine methylation involves the mismatch repair system.

Footnotes

    • Received December 29, 1997.
    • Accepted May 5, 1998.
  • Send reprint requests to: Dr. Stefania D’Atri, IDI-IRCCS, Laboratory of Clinical Pharmacology, Via dei Monti di Creta 104, 00167 Rome, Italy. E-mail: s.datri{at}idi.it

  • This work was supported in part by a grant from the Istituto Superiore di Sanitá (Rome, Italy) (Italy-USA Therapy of Tumors Program) and in part by the Italian Ministry of Health. J.J. acknowledges the generous support of the Schweizerischer Nationalfonds zur Förderung der Wisseschaftlichen Forschung. Part of this work was presented at the 88th Annual Meeting of the American Association for Cancer Research (1997 April 12–16; San Diego, CA) (D’Atriet al., 1997).

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Molecular Pharmacology: 54 (2)
Molecular Pharmacology
Vol. 54, Issue 2
1 Aug 1998
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Research ArticleArticle

Involvement of the Mismatch Repair System in Temozolomide-Induced Apoptosis

Stefania D’Atri, Lucio Tentori, Pedro Miguel Lacal, Grazia Graziani, Elena Pagani, Elena Benincasa, Giovanna Zambruno, Enzo Bonmassar and Josef Jiricny
Molecular Pharmacology August 1, 1998, 54 (2) 334-341; DOI: https://doi.org/10.1124/mol.54.2.334

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Research ArticleArticle

Involvement of the Mismatch Repair System in Temozolomide-Induced Apoptosis

Stefania D’Atri, Lucio Tentori, Pedro Miguel Lacal, Grazia Graziani, Elena Pagani, Elena Benincasa, Giovanna Zambruno, Enzo Bonmassar and Josef Jiricny
Molecular Pharmacology August 1, 1998, 54 (2) 334-341; DOI: https://doi.org/10.1124/mol.54.2.334
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