COMBINED EFFECTS OF ANGIOSTATIN AND IONIZING-RADIATION IN ANTITUMOR THERAPY

Angiogenesis, the formation of new capillaries from pre-existing vesse ls, is essential for tumour progression(1-5). Angiostatin, a proteolyt ic fragment of plasminogen(6) that was first isolated from the serum a nd urine of tumour-bearing mice(7), inhibits angiogenesis and thereby growth of primary(8) and metastatic(7,9,10) tumours. Radiotherapy is i mportant in the treatment of many human cancers, but is often unsucces sful because of tumour cell radiation resistance(11,12). Here we combi ne radiation with angiostatin to target tumour vasculature that is gen etically stable and therefore less likely to develop resistance(13-15) . The results show an antitumour interaction between ionizing radiatio n and angiostatin for four distinct tumour types, at doses of radiatio n that are used in radiotherapy. The combination produced no increase in toxicity towards normal tissue. In vitro studies show that radiatio n and angiostatin have combined cytotoxic effects on endothelial cells , but not tumour cells. In vivo studies show that these agents, in com bination, target the tumour vasculature. Our results provide support f or combining ionizing radiation with angiostatin to improve tumour era dication without increasing deleterious effects.