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

Anticancer Res. Sep-Oct 2000;20(5B):3363-73.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / 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
  • Interferon-gamma / metabolism
  • Picibanil / therapeutic use
  • Recombinant Proteins
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Tacrolimus / administration & dosage
  • Tumor Cells, Cultured / drug effects

Substances

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