A combination of cyclosporin-A (CsA) and interferon-gamma (INF-gamma) induces 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 its modulation by cyclosporin-A or tacrolimus (FK-506) were investigated in in 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 gastric 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 endothelial cells (HUVECs) in vitro. Apoptosis was also induced by a combination of rIFN-gamma with FK-506 but not with rapamycin. Next, the apoptosis-inducing effect of endogenous IFN-gamma combined with cyclosporin-A was examined using clinical samples. A streptococcal preparation, OK-432, was administered intraperitoneally for the management of 12 gastric cancer patients with malignant ascites. None of the gascitic fluids obtained before the OK-432 injection showed detectable IFN-gamma level. The OK-432 injection induced a detectable IFN-gamma production ranging from 6 to 89 pg/mL in ascitic fluids from 9 out of the 12 patients. A combination of CsA with ascitic fluids collected 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 apoptosis was also blocked by a specific antibody against human IFN-gamma. These results indicated that both recombinant and endogenous IFN-gamma can induce potent tumor-apoptosis when combined with CsA.
Morisaki
T
T
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan.
Matsunaga
H
H
Beppu
K
K
Ihara
E
E
Hirano
K
K
Kanaide
H
H
Mori
M
M
Katano
M
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001202:Ascitic Fluid / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000008:administration & dosage / Q000378:metabolism; D010844:Picibanil / Q000627:therapeutic use; D011994:Recombinant Proteins; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016559:Tacrolimus / Q000008:administration & dosage; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D011994:Recombinant Proteins; D010844:Picibanil; D007371:Interferon-gamma; D016572:Cyclosporine; D016559:Tacrolimus