Abstract
Temozolomide (TMZ) is a new cytotoxic triazene compound of clinical interest that is able to generate methyl adducts at the O6-guanine of DNA, which can be repaired by O6-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 inhibitor O6-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 of O6-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 that O6-benzylguanine may potentiate this activity.
| Original language | English |
|---|---|
| Pages (from-to) | 1292-1300 |
| Number of pages | 9 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 291 |
| Issue number | 3 |
| Publication status | Published - Dec 1999 |
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ASJC Scopus subject areas
- Pharmacology
Cite this
O6-Benzylguanine enhances the in vitro immunotoxic activity of temozolomide on natural or antigen-dependent immunity. / Alvino, Ester; Pepponi, Rita; Pagani, Elena; Lacal, Pedro Miguel; Nunziata, Corrado; Bonmassar, Enzo; D'Atri, Stefania.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 291, No. 3, 12.1999, p. 1292-1300.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - O6-Benzylguanine enhances the in vitro immunotoxic activity of temozolomide on natural or antigen-dependent immunity
AU - Alvino, Ester
AU - Pepponi, Rita
AU - Pagani, Elena
AU - Lacal, Pedro Miguel
AU - Nunziata, Corrado
AU - Bonmassar, Enzo
AU - D'Atri, Stefania
PY - 1999/12
Y1 - 1999/12
N2 - Temozolomide (TMZ) is a new cytotoxic triazene compound of clinical interest that is able to generate methyl adducts at the O6-guanine of DNA, which can be repaired by O6-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 inhibitor O6-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 of O6-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 that O6-benzylguanine may potentiate this activity.
AB - Temozolomide (TMZ) is a new cytotoxic triazene compound of clinical interest that is able to generate methyl adducts at the O6-guanine of DNA, which can be repaired by O6-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 inhibitor O6-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 of O6-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 that O6-benzylguanine may potentiate this activity.
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M3 - Article
VL - 291
SP - 1292
EP - 1300
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -