The recently described CC chemokine, 6C-kine, is unique in that it contains -six rather than the usual four conserved cysteines typical of this family. Furthermore, murine 6C-kine binds to one of the CXC chemokine receptors CXCR3, in addition to its other known receptor CCR7. We have shown that two other ligands of CXCR3, IP-10 and MIG, are potent inhibitors of tumor growth in severe combined immunodeficiency (SCID) mice. We postulated that murine 6C-kine may also inhibit tumor growth via inhibition of angiogenesis in this model. SCID mice (n=6 per group) inoculated with A549 human lung cancer cells were treated with either 6C-kine (100 ng intra-tumor injection every other day) or control protein for 8 weeks. Tumors from murine 6C-kine-treated mice (288 ± 26 mm³) were significantly smaller than tumors from control treated mice (788 ± 156 mm³, P=0.005). Additionally, murine 6C-kine reduced metastases compared with controls (0.5 ± 0.3 vs 3.0 ± 1.2 metastases per animal, P=0.05). Tumor vascularity (as assessed by vessel density counting) was reduced in murine 6C-kine-treated mice compared with controls. Murine 6C-kine had no direct effect on proliferation of A549 cells, and there were no differences in the infiltration of leukocyte sub-populations, assessed by flow cytometry, in the treatment groups. Interestingly, human 6C-kine, unlike murine 6C-kine, does not bind CXCR3 and had no anti-tumor effect in the same model. These data suggest that murine 6C-kine has anti-tumor effects independent of its leukocyte-recruiting activity. Furthermore, while not confirmatory, these data lend further support to the fact that CXCR3 may be the receptor for angiostatic CXC chemokines.