The combined treatment of PTK and PKI in the nude mouse model provided additive effects with further reductions in microvessel density compared to single inhibitor treatments. Inhibition of signalling molecules downstream of VEGFR also present viable treatment options.Inhibitors of PKC decreased VEGFA induced endothelial cell proliferation and permeability. Clinical trials of a PKC inhibitor are underway for treatment of diabetic macular edema. NK, an intramolecular fragment of HGF that contains four kringles domains, competes with HGF for binding to HGFR, and thus is an antagonist of HGFR signaling.Antibodies to v, blocked Methscopolamine angiogenesis induced by FGF, but also had no effect on preexisting vessels. Although drugrelated toxicity was minimal, of the patients tested, only one showed a partial response and seven patients demonstrated disease stability. BK is a proangiogenic peptide and its receptors are expressed on many cancer cells.Promising results were observed with use of a monoclonal antibody that targets the BK precursor, kininogen.Longterm disease stability, as measured by less than growth in months, was observed in of the patients. Heptaminol hydrochloride recombinant endostatin recently entered phase I clinical trials.Patients received intravenous infusion of recombinant human endostatin daily for a day cycle, with very low drugrelated toxicity.However, no clinical responses were observed in the patients treated, although several patients exhibited reductions in VEGF levels promotes endothelial cell apoptosis, and thus may be used to slow the progression of proliferative diabetic retinopathy.However, recent observations of elevated PEDF in ischemic retinas have questioned the efcacy of PEDF as an angiogenesis inhibitor. NS is a selective COX inhibitor that was shown initially to suppress VEGF expression found that NS did not affect tumor cell secretion of angiogenic factors at concentrations that produced maximal prostaglandin inhibition and that at higher concentrations, NS actually increased angiogenic factor production.Marimastat is an orally administered, synthetic broad spectrum inhibitor of MMP activity, M.Marimastat has been shown to inhibit tumor growth and metastatic spread, but has not induced tumor regression. CD cells harboring a herpes simplex viral vector homed to areas of tumor angiogenesis in a rhesus model, and tumor death occurred when animals subsequently were administered the antiherpes simplex virus drug ganciclover. Subsequent treatment of the mice with uorocytosine resulted in tumor death due to production of uorouracil in cells expressing CDURPT.Mice that received the embryonic EPC therapy lived slightly longer than controls but no cures were achieved. This has led to the strategy of simultaneously targeting the function of multiple angiogenic mediators.Clinical trials have found the greatest effect on tumor growth when antiangiogenesis therapies have been applied in combination with conventional radiation andor chemotherapy treatments. Tumor blood vessels tend to be highly disorganized, tortuous, with excessive permeability and fewer supporting cells such as pericytes and smooth muscle cells than normal tissue vasculature. It has been proposed that antiangiogenic therapies normalize the tumor vasculature by reducing vessel tortuosity, decreasing permeability, and pruning unnecessary branches, all of which improve the delivery of chemotherapy agents. In addition, conventional chemotherapy drugs have antiangiogenic effects when administered metronomically, or in small frequent doses, due to sensitivity of tumor endothelial cells to the drugs.