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 upregu lated expression of matrix metalloproteinase (MMP)-9, but not MMP-2 in cult ure supernatants, They also produced increased amounts of vascular endothel ial growth factor (VEGF), which was not associated with alterations in isof orms of VEGF mRNA, PCI-43p3 cells attached to cultured mesothelial cell mon olayers more readily than did the parent PCI-43 tells. The angiogenesis inh ibiting agent, TNP-470, at 30 mg/kg was administered to the model mice, res ulting in a prominent suppression of the establishment of peritoneal nodule s, The suppression was dependent on the duration of TNP-470 treatment. TNP- 470 treatment significantly suppressed proliferation of tumor cells in diss eminated nodules, assessed in terms of immunostaining for proliferating cel l nuclear antigen (PCNA), TNP-470 did not affect the in vitro attachment be tween PCI-43p3 and mesothelial cells. The combined data show that anti-angi ogenic treatment profoundly suppresses the in vivo process of peritoneal di ssemination.