Vascularization of many solid tumors occurs in vivo as a consequence of the vectorial growth of host capillary endothelial cells along a concentration gradient of a tumor-produced, diffusible angiogenesis factor(s). The identification of one of these factors as """"""""angiogenic copper"""""""" raises the possibility that copper chelators can function as antiangiogenic agents.
The specific aims of this proposed Phase I study are: 1) to test various copper chelators for possible antiangiogenic effects in the chicken chorioallantoic membrane (CAM) assay; 2) to employ as angiogenic stimulators in this system copper-heparin, a polypeptide angiogen derived from nervous tissues, a low mol.wt. angiogen derived from the Walker 256 rat tumor, and viable tumor cells from this same source; 3) to establish, using in vitro methods, whether agents active in the CAM assay are inhibiting vascular endothelial cell (EC) migration and/or proliferation or are toxic to EC and/or tumor cells; and 4) based on the outcome of the studies related to the first three objectives, to prepare heparin- (or heparin fragment-) linked chelators and employ these novel substances in analogous studies. Results from these studies should allow identification of new antiangiogenic agents. These substances can be screened more thoroughly in a Phase II study for their anticancer properties against various tumors in experimental animals. Thus, the ultimate objective of these studies is to define novel antiangiogenic agents that will provide improved means for controlling tumor growth and spread.
