title: Mechanical analysis of tumor growth regression by the cyclooxygenase-2 inhibitor, DFU, in a Walker256 rat tumor model: importance of monocyte chemoattractant protein-1 modulation.
abstract: Cyclooxygenase (COX)-2 inhibition results in tumor regression; however, little is known about the mechanism. In the present study, using a Walker256 tumor model and a rat bone marrow-derived endothelial cell line TR-BME-2, we analyzed the effects of a new selective COX-2 inhibitor, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2-(5H)-furanone (DFU), on the production of chemokines and growth factors and on the neovascularization. The oral administration of DFU (5 mg/kg/d) significantly suppressed the tumor growth with decreasing microvessel density in vivo, although it showed no direct inhibition of Walker256 cell proliferation in vitro. It was newly found that the recruitment of systemically injected TR-BME-2 cells into the tumor site was significantly inhibited by DFU treatment. In addition, we found that DFU significantly reduced the production of monocyte chemoattractant protein-1 (MCP-1) both in tumor tissues and in the systemic circulation (P < 0.001 and P < 0.001, respectively). Such reduction was not observed in other chemotactic factors, vascular endothelial growth factor and stromal cell-derived factor-1. The induced chemotaxis of TR-BME-2 by serum of tumor-bearing rats was significantly reduced in DFU-treated rat serum, although DFU showed no direct inhibition for TR-BME-2 cells, either cell growth or chemotaxis. Treatment with neutralizing antibodies to soluble mediators, including MCP-1, significantly suppressed the chemotaxis. Regarding the down-regulation machinery of MCP-1 production in vivo, tumor-associated macrophages seem to play crucial roles, because DFU eliminated MCP-1 production in the activated macrophages remarkably but not in Walker256 tumor cells in vitro. In conclusion, COX-2 inhibitor DFU exerts tumor regression activity in a Walker256 tumor model by suppressing MCP-1 production in tumor tissues and in the circulation.
authors.affiliation: Department of Surgery, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Muta
authors.forename: Gaku
authors.initials: G
authors.lastname: Matsumoto
authors.forename: Emi
authors.initials: E
authors.lastname: Nakashima
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000187:drug effects / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005663:Furans / Q000494:pharmacology*; D007150:Immunohistochemistry; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018925:Chemokines; D052246:Cyclooxygenase 2 Inhibitors; D005663:Furans