title: cis-Diamminedichloroplatinum and 5-fluorouracil are potent inducers of the cytokines and natural killer cell activity in vivo and in vitro.
abstract: It has been reported that certain chemotherapeutic agents exhibit effects that enhance the antitumor host responses in the patients with malignant diseases. In the present study, we investigated whether cis-diamminedichloroplatinum (cisplatin) and 5-fluorouracil (5-FU) may induce cytokines and effector cells with antitumor efficacy in vivo and in vitro. The cultivation of human peripheral blood mononuclear cells (PBMC) in the presence of cisplatin (0-1.0 microg/ml) or 5-FU (0-5.0 microg/ml) resulted in the significant augmentation of natural killer (NK) and lymphokine-activated killer (LAK) cell activities as well as generation of interferon (IFN) gamma, tumor necrosis factor (TNF) alpha, beta interleukin(IL)-1beta, IL-6 and IL-12 in vitro. In addition, all of these activities were almost completely neutralized by addition of anti-asialoGM1 antibody and complement (P < 0.05). In an in vivo model, the administration of anti-asialoGM1 antibody significantly shortened the survival time extended by the treatment with cisplatin or 5-FU (P < 0.05), both on nude mice bearing salivary gland tumors and on syngeneic MethA-tumor-bearing BALB/c mice. Furthermore, high levels of NK and LAK activities and significant increases of the numbers of cells positive for asialoGM1, IFNgamma, TNFalpha, or IL-1beta were detected in the spleen cells derived from animals given cisplatin or 5-FU as compared with those given saline (P < 0.001-0.05). These findings clearly indicate that cisplatin and 5-FU are potent inducers of several types of cytokines and effector cells carrying antitumor activity mediated by asialoGM1-positive cells (mainly NK cells) for the most part, and that these abilities are closely associated with the in vivo antitumor effect of these agents.
authors.affiliation: Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Japan. mokamoto@dent.tokushima-u.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Okamoto
authors.forename: H
authors.initials: H
authors.lastname: Kasetani
authors.forename: R
authors.initials: R
authors.lastname: Kaji
authors.forename: H
authors.initials: H
authors.lastname: Goda
authors.forename: G
authors.initials: G
authors.lastname: Ohe
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: M
authors.initials: M
authors.lastname: Sato
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D005677:G(M1) Ganglioside / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D016207:Cytokines; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; D002945:Cisplatin; D005472:Fluorouracil