cis-Diamminedichloroplatinum and 5-fluorouracil are potent inducers of the cytokines and natural killer cell activity in vivo and in vitro.
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.
Okamoto
M
M
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Japan. mokamoto@dent.tokushima-u.ac.jp
Kasetani
H
H
Kaji
R
R
Goda
H
H
Ohe
G
G
Yoshida
H
H
Sato
M
M
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
D000906:Antibodies; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D016207:Cytokines; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; D002945:Cisplatin; D005472:Fluorouracil