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

Abstract

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.

• Authors: T Morisaki, H Matsunaga, K Beppu, E Ihara, K Hirano, H Kanaide, M Mori, M Katano
• Journal: Anticancer research (Anticancer Res) 2000 Sep- Oct Vol. 20 Issue 5B Pg. 3363-73 ISSN: 0250-7005 [Print] Greece
• PMID: 11131636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Immunosuppressive Agents
• Recombinant Proteins
• Picibanil
• Interferon-gamma
• Cyclosporine
• Tacrolimus

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Ascitic Fluid (metabolism)
• Cyclosporine (administration & dosage)
• Drug Interactions
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunosuppressive Agents (administration & dosage)
• Injections, Intraperitoneal
• Interferon-gamma (administration & dosage, metabolism)
• Picibanil (therapeutic use)
• Recombinant Proteins
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Tacrolimus (administration & dosage)
• Tumor Cells, Cultured (drug effects)