Tumor growth is accompanied by angiogenesis, and because surgical removal of certain tumors may lead to rapid growth of remote metastases, endogenous angiogenesis inhibitors may be secreted from the tumor. The endogenous angiogenesis inhibitor, angiostatin, was identified in urine in 1994, and a more potent angiogenesis inhibitor, endostatin, was discovered in 1997 in the conditioned media of cultured hemangioblastoma cells. Endostatin is a 20-kDa carboxy-terminal proteolytic fragment derived from the first noncollagenous domain of collagen XVHL Because tumor growth depends on angiogenesis, endostatin was thought to be a promising factor for inhibiting tumor growth. Indeed, many animal and human tumors have been inhibited by the administration of endostatin in animal studies; however, the results of several clinical studies were disappointing, and the clinical trials of endostatin were terminated at early phase n in the United States. The failure of the clinical studies is attributable, at least in part, to the failure of an appropriate trial design, including administration regimen, patient selection and the establishment of a biologically effective dosage. Only Endostar, a N-terminal modified endostatin, is used in clinical trials in China, although its precise effectiveness is unknown.
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