Antiangiogenic treatment with three thrombospondin-1 type 1 repeats versus gemcitabine in an orthotopic human pancreatic cancer model.
OBJECTIVE
In this study, we investigated the antitumor efficacy of thrombospondin-1 three type 1 repeats (3TSR), the antiangiogenic domain of thrombospondin-1, in comparison and in combination with gemcitabine, in an orthotopic pancreatic cancer model.


METHODS
Human pancreatic cancer cells were injected into the pancreas of severe combined immunodeficient mice. The animals were treated with 3TSR, gemcitabine, 3TSR plus gemcitabine, or vehicle for 3 weeks. Subsequently, the effects of 3TSR and/or gemcitabine on tumor growth, tumor necrosis, microvessel density, cancer cell proliferation, apoptosis, and endothelial cell apoptosis were analyzed.


RESULTS
After 3 weeks of treatment, 3TSR reduced tumor volume by 65%, and gemcitabine by 84%. Tumor volume was not statistically different between gemcitabine group and combinatorial treatment group. Extensive necrotic areas were observed in tumors from 3TSR-treated mice, whereas tumors from gemcitabine and combinatorially treated mice were less necrotic than control tumors. 3TSR reduced tumor microvessel density and increased tumor blood vessel endothelial cell apoptosis. In contrast, gemcitabine induced apoptosis and inhibited proliferation of cancer cells.


CONCLUSIONS
3TSR, the antiangiogenic domain of thrombospondin-1, showed comparable antitumor efficacy to gemcitabine in a human pancreatic cancer orthotopic mouse model. No synergistic effect was found when the two drugs were combined and possible reasons are discussed in detail. A delicate balance between normalization and excessive regression of tumor vasculature is important when initiating alternative combinatorial regimens for treatment of patients with pancreatic cancer.
Zhang
Xuefeng
X
Department of Surgery and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Galardi
Eric
E
Duquette
Mark
M
Lawler
Jack
J
Parangi
Sareh
S
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009336:Necrosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D019700:Thrombospondin 1 / Q000737:chemistry* / Q000494:pharmacology; D013997:Time Factors; D000093542:Gemcitabine
D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011994:Recombinant Proteins; D019700:Thrombospondin 1; D003841:Deoxycytidine; D000093542:Gemcitabine