title: Influence of anticancer agents on cell survival, proliferation, and CD4+CD25+Foxp3+ regulatory T cell-frequency in human peripheral-blood mononuclear cells activated by T cell-mitogen.
abstract: Many anticancer agents currently used are considered to be cytotoxic not only to cancer cells but also to functional immune cells. To learn more about the immunosuppressive adverse influence of chemotherapeutic drugs in cancer chemotherapy, we examined the effects of arsenic trioxide, dacarbazine, 5-fluorouracil, and methotrexate on the survival, proliferation, cytokine production, and CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cell-frequency in human peripheral blood mononuclear cells (PBMCs) activated by T cell mitogen in vitro. Arsenic trioxide, dacarbazine, and 5-fluorouracil increased trypan-blue stained (dead) cell rates and suppressed the mitogen-activated proliferation of PBMCs significantly at 1-100μM (p<0.05). Methotrexate also significantly increased the percentages of dead cells and suppressed the mitogen-activated PBMC-proliferation at concentrations of more than 0.05μM (p<0.01). Arsenic trioxide significantly inhibited the production of interferon γ, interleukin (IL)-4, -6, and -10 from the activated PBMCs at 5μM (p<0.05). In contrast, the anticancer agents significantly increased Treg cell-frequency in the activated PBMCs at concentrations of more than 0.1μM for methotrexate, 5μM for arsenic trioxide and 5-fluorouracil, and 50μM for dacarbazine, respectively (p<0.05). These agents did not significantly influence the production of transforming growth factor (TGF) β from the activated PBMCs at a concentration range of 0.05-50μM. Our data suggest that the anticancer agents: arsenic trioxide, dacarbazine, 5-fluorouracil, and methotrexate attenuate T cell mediated immunity by not only inhibiting the proliferative response of T cells but by also increasing the frequency of Treg cells, which may result in the suppression of the effector T cell function.
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Tohyama
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tanaka
authors.forename: Kenji
authors.initials: K
authors.lastname: Onda
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hirano
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D003606:Dacarbazine / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology; D010087:Oxides / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D016207:Cytokines; D007166:Immunosuppressive Agents; D008934:Mitogens; D010087:Oxides; D003208:Concanavalin A; D003606:Dacarbazine; D000077237:Arsenic Trioxide; D005472:Fluorouracil; D008727:Methotrexate