Angiogenesis inhibitors in genitourinary cancers.

Despite much enthusiasm, no clear clinical benefit to any antiangiogenic agent has yet been demonstrated. Phase I trials demonstrate that endostatin, an endothelial cell toxin, can be administered safely, but no obvious anti-tumor effects were observed. Certain matrix metalloproteinase inhibitors appear ineffective, but later generation inhibitors with less systemic toxicity continue to be investigated. There are occasional responses to thalidomide either singly or in combination, but its pharmacology and mechanism of action remain unclear. A randomized study with the anti-VEGF antibody bevacizumab suggests that VEGF pathway is an important target in renal cell cancer. VEGF receptor tyrosine kinase inhibitors continue to be developed, but one of the first compounds SU5416 has had minimal clinical effects. Clinical trial designs that address the stable disease endpoint should thus be investigated and the randomized discontinuation design has already been tested. Pharmacodynamic markers that reflect antiangiogenic drug effect also need to be developed, but the putative ones, including circulating proangiogenic factors, tumor microvessel density, and dynamic contrast MRI have not yet proven to be useful.