O(6)-benzylguanine enhances the in vitro immunotoxic activity of temozolomide on natural or antigen-dependent immunity.
Temozolomide (TMZ) is a new cytotoxic triazene compound of clinical interest that is able to generate methyl adducts at the O(6)-guanine of DNA, which can be repaired by O(6)-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 O(6)-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 O(6)-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 O(6)-guanine methylation in the immunosuppressive effects of TMZ was further confirmed by the finding that O(6)-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 O(6)-benzylguanine may potentiate this activity.
Alvino
E
E
Institute of Experimental Medicine, National Council of Research, Rome, Italy.
Pepponi
R
R
Pagani
E
E
Lacal
P M
PM
Nunziata
C
C
Bonmassar
E
E
D'Atri
S
S
D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D002460:Cell Line; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007376:Interleukin-2 / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D000077204:Temozolomide