Angiostatin and angiostatin-related proteins

The study of angiogenesis, and the promise of angiogenesis inhibition as a means of cancer therapy, has dramatically accelerated in the last several y ears. The discovery and publication of angiostatin by O'Reilly and colleagu es in Judah Folkman's lab in 1994 has greatly contributed to this progress. Angiostatin is a kringle-containing fragment of plasminogen, which is a po tent inhibitor of angiogenesis in-vivo, and selectively inhibits endothelia l cell proliferation and migration in-vitro. There have been a number of pr oposed proteolytic mechanisms by which plasminogen is cleaved to form angio statin, and the resulting cleavage products contain different NH2 and COOH termini of the angiostatin. Therefore, it is possible that there are more t han one angiostatin isoforms (or angiostatin-related proteins) which occur in one or more normal or pathophysiological situations. It is also possible that some of the proteolytic processes which can convert plasminogen to an giostatin-like proteins are simply laboratory artifacts. Angiostatin-relate d proteins exert potent endothelial cell inhibitory activity, including the induction of apoptosis, and inhibition of migration, and the intact kringl e structures are believed to be necessary for the antiangiogenic activity. Efforts are now underway to translate the understanding of the biology of a ngiostatin to clinical practice, which includes phase 1 clinical trials wit h recombinant angiostatin K1-3 (kringles 1-3) as well as phase 1 trials of an Angiostatin Cocktail, which induces the direct in vivo conversion of pla sminogen to angiostatin 4.5 (kringles 1-4, plus most of kringle 5). The tra nslation of the basic science of angiostatin and angiostatin-related protei ns to clinical trial promises to provide an important new tool in the treat ment of cancer by inhibition of angiogenesis.