Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice

Angiostatin and endostatin are potent endothelial cell growth inhibitors th at have been shown to inhibit angiogenesis in vivo and tumor growth in mice . However, tumor shrinkage requires chronic delivery of large doses of thes e proteins. Here we report synergistic antitumor activity and survival of a nimals when these factors are delivered in combination to tumors by retrovi ral gene transfer. We have demonstrated this efficacy in both murine leukem ia and melanoma models. Complete loss of tumorigenicity was seen in 40% of the animals receiving tumors transduced by the combination of angiostatin a nd endostatin in the leukemia model. The synergy was also demonstrated in v itro on human umbilical vein endothelial cell differentiation and this anti angiogenic activity may suggest a mechanism for the antitumor activity in v ivo. These findings imply separate pathways by which angiostatin and endost atin mediate their antiangiogenic effects. Together, these data suggest tha t a combination of antiangiogenic factors delivered by retroviral gene tran sfer may produce synergistic antitumor effects in both leukemia and solid t umors, thus avoiding long-term administration of recombinant proteins. The data also suggest that novel combinations of antiangiogenic factors deliver ed into tumors require further investigation as therapeutic modalities.