|
|
|
|
|
|
||
|
|
||||
|
|
||||
|
||||
Tumor Biology |
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 BT4Cn 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.
Blezinger, P., Wang, J., Gondo, M., Quezada, A., Mehrens, D., French, M., Singhal, A., Sullivan, S., Rolland, A., Ralston, R., and Min, W. (1999) Systemic inhibition of tumor growth and tumor metastases by intramuscular administration of the endostatin gene. Nat. Biotechnol. 17, 343-348.[CrossRef][Web of Science][Medline]
Boehm, T., Folkman, J., Browder, T., and O'Reiley, M.S. (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390, 404-407.[CrossRef][Medline]
Boehm, T., O'Reilley, M.S., Keough, K., Shiloach, J., Shapiro, R., and Folkman, J. (1998) Zinc-binding of endostatin is essential for its antiangiogenic activity. Biochem. Biophys. Res. Commun. 252, 190-194.[CrossRef][Web of Science][Medline]
Buckberg, G.D., Luck, J.C., Payne, D.B., Hoffmann, J.I.E., Archie, J.P., and Fixler, D.E. (1971) Some sources of error in measuring regional blood flow with radioactive microspheres. J. Appl. Physiol. 31, 598-604.
Chen, Q.R., Kumar, D., Stass, S.A., and Mixson, A.J. (1999) Liposomes complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice. Cancer Res. 59, 3308-3312.
Dhanabal, M., Ramchandran, R., Waterman, M.J., Lu, H., Knebelmann, B., Segal, M., and Sukhatme, V.P. (1999) Endostatin induces endothelial cell apoptosis. J. Biol. Chem. 274, 11721-11726.
Ehleben, W., Porwol, T., Fandrey, J., Kummer, W., and Acker, H. (1997) Cobalt and desferrioxamine reveal crucial members of the oxygen sensing pathway in HepG2 cells. Kidney Int. 51, 483-491.[Web of Science][Medline]
Feldman, A.L., Restifo, N.P., Alexander, H.R., Barlet, D.L., Hwu, P., Seth, P., and Libutti, S.K. (2000) Antiangiogenic gene therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice. Cancer Res. 60, 1503-1506.
Folkman, J. (1990) What is the evidence that tumors are angiogenesis dependent? J. Natl. Cancer Inst. 82, 4-6.
Gavrieli, Y., Sherman, Y., and Ben-Sasson, S.A. (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119, 493-501.
Hohenester, E., Sasaki, T., Olsen, B.R., and Timpl, R. (1998) Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution. EMBO J. 17, 1656-1664.[CrossRef][Web of Science][Medline]
Iversen, P.O., Nicolaysen, G., and Benestad, H.B. (1992) Blood flow to bone marrow during development of anemia or polycythemia in the rat. Blood 79, 594-601.
Lorensen, W.E., and Cline, H.E. (1987) Marching cubes: A high resolution 3D surface construction algorithm. Comput. Graph. 21, 163-169.[CrossRef]
Kim, Y.M., Jang, J.W., Lee, O.H., Yeon, J., Choi, E.Y., Kim, K.W., Lee, S.T., and Kwon, Y.G. (2000) Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase. Cancer Res. 60, 5410-5413.
MacDonald, N.J., Shivers, W.Y., Narum, D.L., Plum, S.M., Wingard, J.N., Fuhrmann, S.R., Liang, H., Holland-Linn, J., Chen, D.H.T., and Sim, B.K.L. (2001) Endostatin binds tropomyosin: A potential modulator of the antitumor activity of endostatin. J. Biol. Chem. 276, 25190-25196.
Mella, O., Bjerkvig, R., Schem, B.C., Dahl, O., and Laerum, O.D. (1990) A cerebral glioma model for experimental therapy and in vivo invasion studies in syngeneic BD IX rats. J. Neurooncol. 2, 93-104.
O'Reilly, M.S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W.S., Flynn, E., Birkhead, J.R., Olsen, B.R., and Folkman, J. (1997) Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277-285.[CrossRef][Web of Science][Medline]
Porwol, T., Merten, E., Opitz, N., and Acker, H. (1996) Three-dimensionalimaging of rhodamine 123 fluorescence distribution in human melanoma cells by means of confocal laser scanning microscopy. Acta Anat. 157, 116-125.[Web of Science][Medline]
Read, T.-A., Sorensen, D.R., Mahesparan, R., Enger, P.O., Timpl, R., Olsen, B.R., Hjelstuen, M.H., Haraldseth, O., and Bjerkvig, R. (2001) Local endostatin treatment of gliomas administered by microencapsulated producer cells. Nat. Biotechnol. 1, 29-34.
Rehbinder, C., Baneux, P., Forbes, D., van Herck, H., Nicklas, W., Rugaya, Z., and Winkler, G. (1996) FELASA recommendations for the health monitoring of mouse, rat, hamster, gerbil, guinea pig and rabbit experimental units. Lab. Anim. 30, 193-208.
Sasaki, T., Fukai, N., Mann, K., Gohring, W., Olsen, B.R., and Timpl, R. (1998) Structure, function and tissue forms of the C-terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin. EMBO J. 17, 4249-4256.[CrossRef][Web of Science][Medline]
Schuier, F.J., Jones, S.C., Fedora, T., and Reivich, M. (1987) 14C-iodoantipyrine and microsphere blood flow estimates in the cat brain. Am. J. Physiol. 253, 1289-1297.
Shichiri, M., and Hirata Y. (2001) Antiangiogenesis signals by endostatin. FASEB J. 15, 1044-1053.
Sim, B.K.L., Vogler W.E., Zhou, X.H., Liang, H., Madsen, J.W., Luu, K., O'Reilly, M.S., Tomaszewsky, J.E., and Fortier, A.H. (1999) Zinc ligand-disrupted recombinant human endostatin: Potent inhibitor of tumor growth, safety and pharmacokinetic profile. Angiogenesis 3, 41-51.[CrossRef][Medline]
Strohmayer, A.R., Porwol, T., Acker, H., and Spiess, E. (1997) Tomography of cells by confocal laser scanning microscopy and computer-assisted three-dimensional image reconstruction: Localization of cathepsin B in tumor cells penetrating collagen gels in vitro. J. Histochem. Cytochem. 45, 975-983.
Yamaguchi, N., Anand-Apte, B., Lee, M., Sasaki, T., Fukai, N., Shapiro, R., Que, I., Lowik, C., Timpl, R., and Olsen, B.R. (1999) Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J. 18, 4414-4423.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  T. A. Rege, C. Y. Fears, and C. L. Gladson Endogenous inhibitors of angiogenesis in malignant gliomas: Nature's antiangiogenic therapy Neuro-oncol, April 1, 2005; 7(2): 106 - 121. [Abstract] [PDF]
|
|
|
|
 |
|
 D. K. Skovseth, M. J. T. Veuger, D. R. Sorensen, P. M. De Angelis, and G. Haraldsen Endostatin dramatically inhibits endothelial cell migration, vascular morphogenesis, and perivascular cell recruitment in vivo Blood, February 1, 2005; 105(3): 1044 - 1051. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. O. Schmidt, M. Ziu, G. Carrabba, C. Giussani, L. Bello, Y. Sun, K. Schmidt, M. Albert, P. Mcl. Black, and R. S. Carroll Antiangiogenic Therapy by Local Intracerebral Microinfusion Improves Treatment Efficiency and Survival in an Orthotopic Human Glioblastoma Model Clin. Cancer Res., February 15, 2004; 10(4): 1255 - 1262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ortega and Z. Werb New functional roles for non-collagenous domains of basement membrane collagens J. Cell Sci., November 15, 2002; 115(22): 4201 - 4214. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
