A combination of cyclosporin-A (CsA) and interferon-gamma (INF-gamma) iduces apoptosis in human gastric carcinoma cells

Modulation of interferon-gamma effect by other drug may enhance its tumor. specific activity. The apoptosis inducing effect of interferon-gamma and it s modulation by cyclosporin-A or tacrolimus (FK-506) were investigated in i n vitro and ex vivo experiments. We found that a combination of cyclosporin -A (CsA) and recombinant interferon-gamma (rIFN-gamma) induced significant apoptosis in all four types of human gasb ic carcinoma cells tested but not in normal cells such as human peripheral blood mononuclear cells (PBMCs), human omentum-derived mesothelial cells, or human umbilical vein endothelia l cells (HUVECs) in vitro. Apoptosis was also induced by a combination of r IFN-gamma with FK-506 but not with rapamycin. Next, the apoptosis-inducing effect of endogenous IFN-gamma combined with cyclosporin-A was examined usi ng clinical smples. A streptococcal preparation, OK-432 was administered in traperitoneally for the management of 12 gastric cancel patients with malig nant ascites. None of the gascitic fluids obtained before the OK-432 inject ion showed delectable IFN-gamma level. The OK-432 injection induced a detec table IFN-gamma production ranging from 6 to 89 pg/mL in ascitic fluids fro m 9 out of the 12 patients. A combination of CsA with ascitic fluids collec ted after but not before OK-432 injection induced significant apoptosis in MK-1 cells, a gastric carcinoma cell line. A positive correlation was found between the IFN-gamma level and CsA-induced apoptosis. The CsA-induced apo ptosis was also blocked by a specific antibody against human IFN-gamma. The se results indicated that both recombinant and endogenous IFN-gamma can ind uce potent tumor-apoptosis when combined with CsA.