Interferon-inducible protein 10 induction and inhibition of angiogenesis in vivo by the antitumor agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)

Abstract

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a drug synthesized in this laboratory that halts tumor blood flow and induces tumor hemorrhagic necrosis in transplantable murine tumors, is known to induce the synthesis of antiangiogenic cytokines in vitro. We have measured the induction of mRNA for modulators of angiogenesis in vivo and investigated whether DMXAA may also have an additional antiangiogenic action through the production of these cytokines. The genes for IFN-alpha and for interferon-inducible protein 10 (IP-10) were strongly induced in both spleen and Colon 38 tumor tissue after DMXAA treatment, whereas that for IFN-gamma was induced in spleen but not in tumor. Expression of mRNA for IFN-beta and for the p35 or the p40 subunits of interleukin 12 was not observed in either tissue. Splenic IP-10 mRNA induction was not a result of IFN-gamma production induced with DMXAA because spleen tissue from DMXAA-treated mice that lacked functional IFN-gamma receptors expressed similar amounts of IP-10 mRNA as those from wild-type mice. A single i.p. injection of DMXAA (20 mg/kg) was sufficient to reduce fibroblast growth factor-induced endothelial cell invasion of Matrigel implants in athymic nude mice by nearly 100%. The inactive analogue 8-methylxanthenone-4-acetic acid did not up-regulate the genes for IP-10 or IFNs and did not inhibit endothelial cell invasion. Antibodies to IP-10 reversed the inhibition of DMXAA of endothelial cell invasion by 58%; antibodies to tumor necrosis factor-alpha, IFN-gamma, and IFN-alpha reversed inhibition by 7%, 5%, and 0%, respectively. The data support the hypothesis that DMXAA, in addition to antivascular effects mediated by tumor necrosis factor-alpha, may have an antiangiogenic effect mediated largely by the induction of IP-10.