COMPARISON OF IMMUNOMODULATIVE EFFECTS OF THE HISTAMINE-2 RECEPTOR ANTAGONISTS CIMETIDINE, RANITIDINE, AND FAMOTIDINE ON PERIPHERAL-BLOOD MONONUCLEAR-CELLS IN GASTRIC-CANCER PATIENTS

Background: Histamine-2 receptor antagonists (H-2-RA) have been shown to improve the function of various parts of the immune system. The proposed mechanism of the immunomodulative effects of H-2-RA has been considered to be the inhibition of suppressor T-lymphocyte activity, an increase in interleukin-2 production, and an enhancement of natural killer cell activity. Most of these studies were done with cimetidine. Comparative data with other H-2-RA are limited and conflict on immunomodulative effects. Comparison of the actions of H-2-RA on the immune system is required. Methods: We compared the immunomodulative effect of the H-2-RAs cimetidine, ranitidine, and famotidine on peripheral blood mononucIear cells (PBMC) in normal controls and patients with gastric cancer. DNA synthesis, cytotoxicity against K562 cells, and the levels of soluble interleukin-2 receptor (sIL-2R) in supernatant were measured after addition of the various H-2-RA to PBMC cultures. Results: Subjects with gastric cancer showed significantly higher levels of suppressor lymphocyte activity than normal controls. These levels were restored to levels of normal controls by the addition of cimetidine. Statistically significant lymphoblastogenesis and cytotoxicity against K562 cells were observed only in cimetidine-treated PBMC (p < 0.05); such effects were not observed in ranitidine- or famotidine-treated PBMC. Significantly increased levels of sIL-2R were found in supernatants obtained from culture flasks treated with cimetidine and phytohemagglutinin or ranitidine and phytohemagglutinin (p < 0.01). Conclusions: Of the three H-2-RAs tested, cimetidine had the strongest and famotidine the weakest immunomoduIating effect. Only cimetidine augmented the cytotoxicity and proliferative response of lymphocyte to mitogen; neither ranitidine nor famotidine had such an effect. These results might be due to their structural differences. In addition, the immunologic effects of H-2-RA are unlikely to be mediated via specific interaction at the H-2 receptor.