BREAST-CANCER ANGIOGENESIS - NEW APPROACHES TO THERAPY VIA ANTIANGIOGENESIS, HYPOXIC ACTIVATED DRUGS, AND VASCULAR TARGETING

Several groups have shown that quantitation of tumor angiogenesis by c ounting blood vessels in primary breast cancer gives an independent as sessment of prognosis. Poor prognosis is associated with high blood ve ssel counts. We have shown that the rate of cell division in endotheli al cells is much higher in breast tumours than in normal breast. Breas t cancer cell lines and primary human breast tumours express a wide ra nge of vascular growth factors, including VEGF, placenta growth factor , pleiotrophin, TGF beta 1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking v ascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than sur amin in vivo but more potent in inhibiting angiogenesis, and these hav e been developed for Phase I. A combination of anti-angiogenesis agent s with drugs activated by hypoxia may also be useful, because anti-ang iogenesis alone may not kill cells, whereas activation of hypoxic drug s could synergize. New endpoints may be necessary because inhibition o f new blood vessel formation may not cause tumour regression. Thus, th e endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angio genesis suggests that this should be a major new therapeutic target.