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Endostatin reduces vascularization, blood flow, and growth in a rat gliosarcoma

Department of Comparative Medicine, Rikshospitalet, University of Oslo, 0027 Oslo, Norway (D.R.S.); Department of Anatomy and Cell Biology, University of Bergen, 5009 Bergen, Norway (T.-A.R., T.P., R.B.); Department of Cell Biology, Harvard Medical School and Harvard-Forsyth Department of Oral Biology, Harvard School of Dental Medicine, Boston, MA 02155 (B.R.O.); Max-Planck-Institut für Biochemie, 82152 Martinsried, Germany (R.T., T.S.); Institute for Nutrition Research, University of Oslo, 0316 Oslo, Norway (P.O.I.); Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway (H.B.B.); EntreMed, Inc., Rockville, MD 20850 (B.K.L.S.)

² Address correspondence and reprint requests to Dag R. Sorensen, Department of Comparative Medicine, Rikshospitalet, University of Oslo, 0027 Oslo, Norway.

Endostatin, the 20-kDa C-terminal fragment of collagen XVIII, has previously been shown to inhibit growth and induce regression of different experimental tumors in rodents. In this study, we show that recombinant murine and human endostatin, produced in 293 EBNA cells and yeast, respectively, inhibit ectotopic as well as orthotopic growing BT₄C_n gliosarcomas in BD-IX rats. In rats in which s.c. gliomas were grown for a total of 29 days, systemic treatment with recombinant murine endostatin induced about 50% reduction of intratumoral blood flow and tumor size after only 10 days of therapy. In contrast, the blood flow to irrelevant organs was unaffected by endostatin, indicating its specificity of action. Tumors were not observed to increase in size or regrow after cessation of therapy. Furthermore, endostatin-treated rats with i.c. tumors had significantly longer survival time than did untreated controls. In the treated rats, endostatin therapy resulted in a reduced tumor blood vessel volume and an increased tumor cell density with an increased apoptotic index within a given tumor volume, as verified by flow cytometry and by staining with deoxynucleotidyltransferase-mediated dUTP nick-end labeling. This work verifies the general anti-angiogenic and antitumor effects of endostatin and indicates that the protein may also be considered as a treatment strategy for malignant brain tumors.

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