Effect of interleukin 12 on tumor induction by 3-methylcholanthrene.
Interleukin (IL)-12 has strong antitumor activity in transplantable tumor systems in the mouse. The present study was designed to determine whether tumor induction by 3-methylcholanthrene (3-MC), a carcinogenic hydrocarbon, can be inhibited by IL-12. BALB/cBy mice were injected subcutaneously with 25 micrograms or 100 micrograms of 3-MC and treated with 100 ng, 10 ng, or 1 ng of IL-12 for 5 days a week for 18 weeks, with a schedule of 3 weeks on and 1 week off. In mice injected with 25 micrograms of 3-MC, treatment with 100 ng of IL-12 delayed tumor appearance and reduced tumor incidence. Tumor appearance was also delayed in mice injected with 100 micrograms of 3-MC and treated with 100 ng of IL-12, but the final tumor incidence was the same as in non-IL-12-treated mice. In contrast to the characteristically round, hard, well-circumscribed, and protruding tumor induced by 3-MC, a percentage of tumors induced in IL-12-treated mice had atypical characteristics: flat, soft, and invasive. Atypical tumors had a longer latent period and were more frequently seen in mice injected with 100 micrograms of 3-MC and treated with 100 ng of IL-12. Interferon gamma, IL-10, and tumor necrosis factor could be induced throughout the treatment period by IL-12, indicating that repeated injections of IL-12 do not induce a state of tachyphylaxis. High production of interferon gamma by CD8 T cells and a TH2-->TH1 or TH0 shift in the cytokine secretion profile of CD4 T cells were also seen in the IL-12-treated mice. IL-12 provides a powerful new way to explore the defensive role of the immune system in tumorigenesis.
Noguchi
Y
Y
Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Jungbluth
A
A
Richards
E C
EC
Old
L J
LJ
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002273:Carcinogens; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology*; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009573:Nitrites / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D016207:Cytokines; D009573:Nitrites; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D008748:Methylcholanthrene; D007371:Interferon-gamma