Background: In previous animal studies, interleukin 12 (IL 12) was sho
wn to inhibit the growth of a wide spectrum of tumors in vivo but to h
ave no direct effect on tumor cells in vitro. Also, contrary to the ex
pectation of a T-cell-mediated effect, the antitumor activity of IL 12
was not completely abrogated in tests of T-cell-deficient mice. These
observations suggest that IL 12 may possess antiangiogenic properties
that account for its tumor-inhibitory effects in vivo. Purpose: Our g
oal was to investigate the hypothesis that IL 12 has antiangiogenic pr
operties. Methods: A model of basic fibroblast growth factor-induced c
orneal neovascularization in mice was used to evaluate the effects of
IL 12 and interferon gamma (IFN gamma) on angiogenesis in vivo. Differ
ent strains of male mice, e.g., immunocompetent C57BL/6 mice, severe c
ombined immune-deficient (SCID) mice, natural killer cell-deficient be
ige mice, and T-cell-deficient nude mice, were treated with IL 12 (1 m
u g/day) intraperitoneally for 5 consecutive days. The extent of neova
scularization in response to a basic fibroblast growth factor pellet a
nd the inhibition of neovascularization by IL 12 or IFN gamma were ass
essed by measuring the maximal vessel length and the corneal circumfer
ence involved in new blood vessel formation. The antitumor activities
of IL 12 and of the angiogenesis inhibitor AGM-1470 were evaluated in
Letvis lung carcinoma-bearing mice. In vitro proliferation studies wer
e performed on bovine capillary endothelial cells, mouse pancreatic is
let endothelial cells, and mouse hemangioendothelioma cells. Results:
IL 12 treatment almost completely inhibited corneal neovascularization
in C57BL/6, SCID, and beige mice. This potent suppression of angiogen
esis was prevented by the administration of IFN gamma-neutralizing ant
ibodies, suggesting that the suppression was mediated through IFN gamm
a. In addition, the administration of IFN gamma reproduced the antiang
iogenic effects observed during treatment with IL 12. Treatment with I
L 12 and AGM-1470 combined did not increase toxicity and showed a tren
d toward enhanced antitumor efficacy in Lewis lung carcinoma-bearing m
ice. Conclusions: IL 12 strongly inhibits neovascularization. This eff
ect is not mediated by a specific cell type of the immune system. Inst
ead, IL 12 has been shown to induce IFN gamma, which, in turn, appears
to play a critical role as a mediator of the antiangiogenic effects o
f IL 12. Implications: Recognition of the mechanisms of the antiangiog
enic properties of IL 12 may be crucial in planning its clinical appli
cations, including a possibility of coadministration with other inhibi
tors of neovascularization.