Combined effects of angiostatin and ionizing radiation in antitumour therapy

Angiogenesis, the formation of new capillaries from pre-existing vessels, is essential for tumour progression1,2,3,4,5. Angiostatin, a proteolytic fragment of plasminogen6 that was first isolated from the serum and urine of tumour-bearing mice7, inhibits angiogenesis and thereby growth of primary8 and metastatic7,9,10 tumours. Radiotherapy is important in the treatment of many human cancers, but is often unsuccessful because of tumour cell radiation resistance11,12. Here we combine radiation with angiostatin to target tumour vasculature that is genetically stable and therefore less likely to develop resistance13,14,15. The results show an antitumour interaction between ionizing radiation and angiostatin for four distinct tumour types, at doses of radiation that are used in radiotherapy. The combination produced no increase in toxicity towards normal tissue. In vitro studies show that radiation and angiostatin have combined cytotoxic effects on endothelial cells, but not tumour cells. In vivo studies show that these agents, in combination, target the tumour vasculature. Our results provide support for combining ionizing radiation with angiostatin to improve tumour eradication without increasing deleterious effects.