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Simplified Production of a Recombinant Human Angiostatin Derivative That Suppresses Intracerebral Glial Tumor Growth¹

Division of Neurosurgery [M. R. R.], and Departments of Neurosciences [P. I. M., R. M. D., M. R. R.] and Pediatrics and Medicine [K. A. H.], Weill Medical College of Cornell University, New York, New York 10021; Departments of Neurology [L. E. A.] and Pathology [S. H. G.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; and Department of Molecular Genetics and Microbiology [K. I. B.], University of Florida College of Medicine, Gainesville, Florida 32610

Angiostatin is an endogenous inhibitor of tumor neovascularization that inhibits the proliferation of endothelial cells. Production of sufficient quantities of biologically active angiostatin by the enzymatic cleavage of plasminogen has proven difficult in that it has delayed clinical testing. We have cloned, expressed, and purified a recombinant human angiostatin derivative (K1-3) using a mammalian expression system. Through the addition of a secretory signal and polyhistidine sequence tag, K1-3 can be purified from postculture medium by simple column chromatography. Purified K1-3 protein is apparently folded in an active conformation, as evidenced by its ability to bind to lysine-Sepharose. In vitro, recombinant K1-3 significantly suppressed endothelial cell proliferation in a dose-dependent manner with an IC₅₀ of 50 nM. Using an animal model of intracranial brain tumors in immune-competent rats, systemic administration of purified recombinant K1-3 resulted in up to 85% suppression of tumor growth (P = 0.011). Growth suppression was accompanied by a 32% decrease (P = 0.01) in tumor neovascularization.

This study demonstrates a simple method to produce a biologically active recombinant angiostatin derivative. The ability to suppress intracerebral tumor growth after systemic administration suggests that K1-3 is likely to have therapeutic value in the treatment of malignant glial tumors.