Protective activity of recombinant murine tumor necrosis factor-alpha and interferon-gamma against experimental murine lung carcinoma metastases.
A variety of biologic and synthetic agents protect BALB/c mice against experimental M109 micrometastases. We have presented evidence that eradication of these metastases is mediated by the activation of host macrophages to the tumoricidal state. We now present evidence that injection of H22, a neutralizing hamster IgG monoclonal antibody to murine interferon-gamma (IFN-gamma; macrophage activating factor), 2 days prior to i.v. tumor inoculation markedly increases the metastatic capacity of M109 lung carcinoma cells. Therefore, we tested several cytokines that induce or mediate macrophage-mediated cytotoxicity, including IFN-gamma, tumor necrosis factor-alpha, and interleukin-1 beta (IL-1 beta), for their ability to inhibit the development of experimental M109 lung metastases. Intraperitoneal treatment with recombinant murine (rMu) IFN-gamma (greater than or equal to 10,000 units/mouse) or recombinant murine TNF-alpha (greater than or equal to 10,000 units/mouse) produced greater than 60% inhibition of metastasis formation. Optimal therapy was observed when cytokines were administered 2 days prior to i.v. tumor cell inoculation. Neither IFN-gamma nor TNF-alpha inhibited colony formation of M109 cells in vitro, suggesting a host-mediated mechanism for antitumor activity. Peritoneal macrophages were primed for tumor cytotoxicity by treatment with either IFN-gamma or TNF-alpha. Intraperitoneal treatment with recombinant human IL-1 beta (1 X 10(5) units) lacked antimetastatic activity. The results further support the role of activated macrophages in the destruction of M109 micrometastases.
Schultz
R M
RM
Department of Immunology Research, Lilly Research Laboratories, Indianapolis, IN 46285.
Altom
M G
MG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000556:secondary; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma