Anti-angiogenic treatment for peritoneal dissemination of pancreas adenocarcinoma: a study using TNP-470.
We established peritoneal dissemination-prone subcultures (PCI-43p3) using nude mice by a repetitive in vivo selection of intraperitoneally inoculated PCI-43, a pancreas adenocarcinoma cell line. The subcultures showed upregulated expression of matrix metalloproteinase (MMP)-9, but not MMP-2 in culture supernatants. They also produced increased amounts of vascular endothelial growth factor (VEGF), which was not associated with alterations in isoforms of VEGF mRNA. PCI-43p3 cells attached to cultured mesothelial cell monolayers more readily than did the parent PCI-43 cells. The angiogenesis inhibiting agent, TNP-470, at 30 mg / kg was administered to the model mice, resulting in a prominent suppression of the establishment of peritoneal nodules. The suppression was dependent on the duration of TNP-470 treatment. TNP-470 treatment significantly suppressed proliferation of tumor cells in disseminated nodules, assessed in terms of immunostaining for proliferating cell nuclear antigen (PCNA). TNP-470 did not affect the in vitro attachment between PCI-43p3 and mesothelial cells. The combined data show that anti-angiogenic treatment profoundly suppresses the in vivo process of peritoneal dissemination.
Kato
H
H
Department of Pathology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.
Ishikura
H
H
Kawarada
Y
Y
Furuya
M
M
Kondo
S
S
Kato
H
H
Yoshiki
T
T
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002448:Cell Adhesion; D003510:Cyclohexanes; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012717:Sesquiterpenes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009363:Neoplasm Proteins; D018809:Proliferating Cell Nuclear Antigen; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018799:Intercellular Adhesion Molecule-1; D020782:Matrix Metalloproteinases; D000077609:O-(Chloroacetylcarbamoyl)fumagillol