Role of endogenous interferon gamma in murine tumor growth and tumor necrosis factor alpha antitumor efficacy.
BACKGROUND
The anticancer role of tumor necrosis factor-alpha (TNF-alpha) has been limited by toxicity. These experiments evaluate blocking endogenous interferon-gamma (IFN-gamma) activity to abrogate TNF-alpha toxicity.


METHODS
C57B1/6 mice bearing MCA 105 tumor were treated with TNF-alpha and anti-IFN-gamma antibody (Ab) to evaluate the effect on the acute lethality of TNF-alpha and their efficacy as evaluated by tumor growth rate, tumor histology, and survival.


RESULTS
Anti-IFN-gamma Ab decreased TNF-alpha lethality. Anti-IFN-gamma Ab alone increased tumor growth significantly more than did nonimmune IgG (p2 < 0.0001). Tumor-bearing mice that received nonimmune IgG and TNF-alpha had slower tumor growth (p2 < 0.02) and a trend toward improved survival (p = 0.07) compared with saline-treated controls. Anti-IFN-gamma Ab abrogated the antitumor effect of TNF-alpha, prevented acute tumor necrosis histologically, and resulted in tumor growth rate and host survival similar to that of controls. The findings in mice that received anti-IFN-gamma Ab and high-dose TNF-alpha were comparable with those in mice that received a lower, equitoxic dose of TNF-alpha alone.


CONCLUSIONS
Blocking endogenous IFN-gamma accelerates tumor growth in this model and partially abrogates the toxic and antitumor activity of exogenous TNF-alpha equally. This suggests that blocking endogenous IFN-gamma activity is not a useful strategy for limiting TNF-alpha treatment toxicity.
Doherty
G M
GM
Department of Surgery, Washington University, St. Louis, Missouri 63110-1093, U.S.A.
Alexander
H R
HR
Merino
M J
MJ
Venzon
D J
DJ
Norton
J A
JA
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology; D005260:Female; D007136:Immunoglobulins / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000627:therapeutic use; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; D007136:Immunoglobulins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma