Endostatin reduces vascularization, blood flow, and growth in a rat gliosarcoma.
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.
Sorensen
Dag R
DR
Department of Comparative Medicine, Rikshospitalet, University of Oslo, Norway.
Read
Tracy-Ann
TA
Porwol
Torsten
T
Olsen
Bjorn Reino
BR
Timpl
Rupert
R
Sasaki
Takako
T
Iversen
Per O
PO
Benestad
Haakon B
HB
Sim
B Kim Lee
BK
Bjerkvig
Rolf
R
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D003094:Collagen / Q000494:pharmacology*; D043170:Collagen Type XVIII; D043169:Endostatins; D005455:Fluorescent Antibody Technique; D018316:Gliosarcoma / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects; D012878:Skin Neoplasms; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D043170:Collagen Type XVIII; D043169:Endostatins; D010446:Peptide Fragments; D003094:Collagen