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Research ArticleArticle

O 6-Benzylguanine Enhances the In Vitro Immunotoxic Activity of Temozolomide on Natural or Antigen-Dependent Immunity

Ester Alvino, Rita Pepponi, Elena Pagani, Pedro Miguel Lacal, Corrado Nunziata, Enzo Bonmassar and Stefania D'Atri
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1292-1300;
Ester Alvino
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Rita Pepponi
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Elena Pagani
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Pedro Miguel Lacal
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Corrado Nunziata
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Enzo Bonmassar
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Stefania D'Atri
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Abstract

Temozolomide (TMZ) is a new cytotoxic triazene compound of clinical interest that is able to generate methyl adducts at theO6-guanine of DNA, which can be repaired byO6-alkylguanine-DNA alkyltransferase (OGAT). It was previously found that triazene compounds are highly immunosuppressive in mice. In the present study, we investigate whether TMZ could affect immune functions of human competent cells and whether methylation of O6-guanine could be involved in the immunosuppressive activity of the drug. Mononuclear cells (MNCs) obtained from peripheral blood of healthy donors were tested for OGAT activity and treated with TMZ alone or combined with the OGAT inhibitorO6-benzylguanine. Control or drug-treated MNCs were then assayed for natural killer activity and for the ability to proliferate and to generate cytotoxic effector cells in response to interleukin-2 or allogeneic MT-2 tumor cells. The results show that TMZ inhibited both proliferation and induction of lytic activity in response to interleukin-2 or allogeneic MT-2 cells. Moreover, an inverse correlation was found between the OGAT activity of MNCs and their sensitivity to TMZ. The involvement ofO6-guanine methylation in the immunosuppressive effects of TMZ was further confirmed by the finding that O6-benzylguanine increased the activity of the drug. On the other hand, the natural killer activity of MNCs was only moderately affected by TMZ, and no relationship was observed between OGAT levels and sensitivity to the drug. These data suggest that in patients with tumors who are undergoing TMZ treatment, the drug may impair immune responses involving cell proliferation, depending on OGAT levels of MNCs, and thatO6-benzylguanine may potentiate this activity.

Footnotes

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

  • ↵1 This work was supported by the Italian Ministry of Health. A portion of the present work has been presented and is available in abstract form [Alvino E, Pepponi R, Pagani E, Ravagnan G, Bonmassar E and D'Atri S (1998) In vitro combined effect of temozolomide (TMZ) and O6-benzylguanine (BG) on cell-mediated immunity of human mononuclear cells (MNCs). Sixth International Conference of Anticancer Research, October 21–25, 1998, Kallithea, Halkidiki, Greece].

  • Abbreviations:
    TMZ
    temozolomide (8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one)
    BG
    O6-benzylguanine
    CM
    complete medium
    CTL
    cytotoxic T lymphocytes
    DTIC
    5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide
    E
    effector
    O6-G
    O6-guanine
    3H-TdR
    [methyl-3H]thymine deoxyriboside
    IL
    interleukin
    LAK
    lymphokine-activated killer
    O6-MeG
    O6-methylguanine
    MNC
    mononuclear cell
    MTIC
    5-(3-methyl-1-triazeno)imidazole-4-carboxamide
    NK
    natural killer
    OGAT
    O6-alkylguanine-DNA alkyltransferase
    T
    target
    • Received May 17, 1999.
    • Accepted August 20, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

O 6-Benzylguanine Enhances the In Vitro Immunotoxic Activity of Temozolomide on Natural or Antigen-Dependent Immunity

Ester Alvino, Rita Pepponi, Elena Pagani, Pedro Miguel Lacal, Corrado Nunziata, Enzo Bonmassar and Stefania D'Atri
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1292-1300;

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Research ArticleArticle

O 6-Benzylguanine Enhances the In Vitro Immunotoxic Activity of Temozolomide on Natural or Antigen-Dependent Immunity

Ester Alvino, Rita Pepponi, Elena Pagani, Pedro Miguel Lacal, Corrado Nunziata, Enzo Bonmassar and Stefania D'Atri
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1292-1300;
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