cis-diaminedichloroplatinum 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 t hat enhance the antitumor host responses in the patients with malignant dis eases. In the present study, we investigated whether cis-diamminedichloropl atinum (cisplatin) and 5-fluorouracil (5-FU) may induce cytokines and effec tor cells with antitumor efficacy in vivo and in vitro. The cultivation of human peripheral blood mononuclear cells (PBMC) in the presence of cisplati n (0-1.0 mu g/ml) or 5-FU (0-5.0 mu g/ml) resulted in the significant augme ntation of natural killer (NK) and lymphokine-activated killer (LAK) cell a ctivities as well as generation of interferon (IFN) gamma, tumor necrosis f actor (TNF) alpha, beta, interleukin(IL)-1 beta, IL-6 and IL-12 in vitro. I n addition, all of these activities were almost completely neutralized by a ddition of anti-asialoGM1 antibody and complement (P < 0.05). In an in vivo model, the administration of anti-asialoGM1 antibody significantly shorten ed 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 Met hA-tumor-bearing BALB/c mice, Furthermore, high levels of NK and LAK activi ties and significant increases of the numbers of cells positive for asialoG M1, IFN gamma, TNF alpha, or IL-1 beta were detected in the spleen cells de rived from animals given cisplatin or 5-FU as compared with those given sal ine (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 car rying antitumor activity mediated by asialoGM1-positive cells (mainly NK ce lls) for the most part, and that these abilities are closely associated wit h the in vivo antitumor effect of these agents.