INTERLEUKIN-12 INHIBITS ANGIOGENESIS INDUCED BY HUMAN TUMOR CELL-LINES IN-VIVO

Tumor cell-induced angiogenesis, i.e., new blood vessel formation with in tumor tissue, is an essential requirement for the growth of solid n eoplasms. Interleukin-12 (IL-12) inhibits growth of a variety of exper imental tumors in vivo. We tested whether antitumor activity of IL-12 is related to the inhibition of angiogenesis induced by tumor cell lin es. Angiogenesis was induced in x-ray immunosuppressed Balb/c mice by intradermal injection of the following human tumor cells: T47D, origin ating from mammary carcinoma; A431, derived from vulval carcinoma; and Sky, established from bowenoid papulosis. Systemic treatment of the m ice with murine IL-12 significantly decreased angiogenesis induced by human tumor cells in a time-and dose-dependent manner. Preincubation o f human cells in vitro with IL-12 did not inhibit tumor cell-induced a ngiogenesis, suggesting that the antiangiogenic capacity of IL-12 is r estricted to in vivo conditions. Treatment of the mice with rat antibo dy against murine interferon-gamma (IFN gamma) resulted in counteracti ng the antiangiogenic effect of murine IL-12. Furthermore, human IFN g amma inhibited the angiogenic activity of human tumor cell lines. This indicates that IFN gamma is a mediator of the antiangiogenic effect o f IL-12. The results show that the mechanism of antitumor action of IL -12 may depend not only on the immunostimulatory activity of this cyto kine but also on its effect on tumor cell-induced angiogenesis. IL-12 should be considered as a potential candidate for the treatment of ang iogenesis-dependent malignancies.