Anti‐angiogenic Treatment for Peritoneal Dissemination of Pancreas Adenocarcinoma: A Study Using TNP‐470

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Abstract
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.

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