Direct effects of recombinant human endostatin on tumor cell IL-8 production are associated with increased endothelial cell apoptosis in an orthotopic model of human pancreatic cancer.
OBJECTIVE
Recombinant human endostatin (rhES) is an antiangiogenic agent derived from collagen XVIII which inhibits tumor growth in subcutaneous models of various human malignancies. However, its effectiveness in an orthotopic xenograft model of an abdominal neoplasm has not been demonstrated.


METHODS
An orthotopic model of pancreatic cancer was established in 6-week-old male athymic mice from either of 2 human cell lines (L3.6pl or BxPC3). Established tumors were treated with 40 mg/kg rhES or vehicle controls for up to 3 weeks. Tumors were analyzed by immunohistochemistry for TUNEL/CD31, IL-8, VEGF, and bFGF. We also measured direct effects of rhES on tumor cell angiogenic factor production by ELISA in vitro.


RESULTS
Overall tumor burden was not reduced with rhES treatment in mice inoculated with either cell line. Peritoneal carcinomatosis in the L3.6pl mice was greater in those treated with rhES than in those treated with normal saline or citrate buffer (p < 0.05). Treatment with rhES lowered IL-8 levels 32-47% in vivo (p < 0.001) and 40-65% in vitro (p < 0.05) in the fast-growing L3.6pl tumors but not in the slow-growing BxPC3 tumors (p < 0.05). rhES also increased the levels of endothelial cell apoptosis 16- to 24-fold in vivo in the L3.6pl mice, but not in the BxPC3 mice (p < 0.05).


CONCLUSIONS
rhES downregulated IL-8 levels and induced endothelial cell apoptosis in the more aggressive cell line in a xenograft model of pancreatic cancer. Nonetheless, these effects were not sufficient to produce significant inhibition of tumor growth.
Raut
Chandrajit P
CP
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Takamori
Ryan K
RK
Davis
Darren W
DW
Sweeney-Gotsch
Bridget
B
O'Reilly
Michael S
MS
McConkey
David J
DJ
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D043169:Endostatins / Q000627:therapeutic use*; D042783:Endothelial Cells / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D016209:Interleukin-8 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000628:therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D043169:Endostatins; D016209:Interleukin-8; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2