EFFECT OF INTERLEUKIN-12 ON TUMOR-INDUCTION BY 3-METHYLCHOLANTHRENE

Interleukin (IL)-12 has strong antitumor activity in transplantable tu mor 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 s ubcutaneously with 25 mu g or 100 mu g 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 sched ule of 3 weeks on and 1 week off. In mice injected with 25 mu g of 3-M C, treatment with 100 ng of IL-12 delayed tumor appearance and reduced tumor incidence. Tumor appearance was also delayed in mice injected w ith 100 mu g of 3-MC and treated with 100 ng of IL-12, but the final t umor incidence was the same as in non-IL-12-treated mice. In contrast to the characteristically round, hard, well-circumscribed, and protrud ing tumor induced by 3-MC, a percentage of tumors induced in IL-12-tre ated mice had atypical characteristics: flat, soft, and invasive. Atyp ical tumors had a longer latent period and were more frequently seen i n mice injected with 100 mu g 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 inj ections of IL-12 do not induce a state of tachyphylaxis. High producti on of interferon gamma by CD8 T cells and a TH2 --> TH1 or TH0 shift i n 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 d efensive role of the immune system in tumorigenesis.