title: Inhibition of urokinase plasminogen activator with a novel enzyme inhibitor, WXC-340, ameliorates endotoxin and surgery-accelerated growth of murine metastases.
abstract: The urokinase plasminogen activator (u-PA) is intimately associated with tumour invasion and metastases. Surgery facilitates accelerated metastatic tumour growth in murine models, a phenomenon related to elevated perioperative bacterial lipopolysaccaride (LPS) and inflammatory cytokine levels. The objectives of the study were to examine the role of u-PA in cytokine-enhanced tumour cell invasion in vitro and surgery-induced accelerated metastatic tumour growth in vivo and to assess the potential benefit of a novel selective u-PA inhibitor WXC-340 in this setting. CT-26 murine colorectal carcinoma cells were stimulated with LPS, tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Cell supernatant u-PA expression and activity were determined using a colorimetric assay and Western blot analysis, respectively. Baseline and cytokine-stimulated in vitro invasion were assessed using ECmatrix invasion chambers. Two established murine models of accelerated metastatic tumour growth were used to investigate the consequences of u-PA inhibition on postoperative metastatic tumour burden. The effect of u-PA inhibition in vitro and in vivo was examined using the novel selective u-PA inhibitor, WXC-340. Proinflammatory cytokine stimulation significantly enhanced in vitro u-PA expression, activity and extracellular matrix invasion by approximately 50% compared to controls (P<0.05). This was abrogated by WXC-340. In vivo WXC-340 almost completely ameliorated both LPS- and surgery-induced, metastatic tumour growth compared to controls (P>0.05). In conclusion, u-PA cascade is actively involved in cytokine-mediated enhanced tumour cell invasion and LPS and surgery-induced metastatic tumour growth. Perioperative u-PA inhibition with WXC-340 may represent a novel therapeutic paradigm.
authors.affiliation: Department of Surgery, Cork University Hospital, Cork, Ireland [2] 2Department of Surgery, University College Cork, Cork, Ireland. sdfkilleen@eircom.net
authors.forename: S D
authors.initials: SD
authors.lastname: Killeen
authors.forename: E J
authors.initials: EJ
authors.lastname: Andrews
authors.forename: J H
authors.initials: JH
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: Wu
authors.forename: W
authors.initials: W
authors.lastname: Schmalix
authors.forename: B
authors.initials: B
authors.lastname: Muehlenweg
authors.forename: H P
authors.initials: HP
authors.lastname: Redmond
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood; D004731:Endotoxins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000473:pathology / Q000601:surgery*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
chemical_list: D016207:Cytokines; D004731:Endotoxins; D004791:Enzyme Inhibitors; D015842:Serine Proteinase Inhibitors; D014568:Urokinase-Type Plasminogen Activator