PMID- 16397051
OWN - NLM
STAT- MEDLINE
DCOM- 20060209
LR  - 20061115
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 12
IP  - 1
DP  - 2006 Jan 1
TI  - 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.
PG  - 264-72
AB  - 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.
FAU - Muta, Mariko
AU  - Muta M
AD  - Department of Surgery, Tokyo Metropolitan Cancer and Infectious Disease Center, 
      Komagome Hospital, Tokyo, Japan.
FAU - Matsumoto, Gaku
AU  - Matsumoto G
FAU - Nakashima, Emi
AU  - Nakashima E
FAU - Toi, Masakazu
AU  - Toi M
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone)
RN  - 0 (Ccl2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokines)
RN  - 0 (Cyclooxygenase 2 Inhibitors)
RN  - 0 (Furans)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Chemokine CCL2/drug effects/*metabolism
MH  - Chemokines/metabolism
MH  - Chemotaxis/drug effects
MH  - Cyclooxygenase 2 Inhibitors/*pharmacology
MH  - Endothelial Cells/drug effects
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Flow Cytometry
MH  - Furans/*pharmacology
MH  - Immunohistochemistry
MH  - Neoplasms, Experimental/blood supply/*drug therapy
MH  - Neovascularization, Pathologic/*drug therapy
MH  - Rats
MH  - Reverse Transcriptase Polymerase Chain Reaction
EDAT- 2006/01/07 09:00
MHDA- 2006/02/10 09:00
CRDT- 2006/01/07 09:00
PHST- 2006/01/07 09:00 [pubmed]
PHST- 2006/02/10 09:00 [medline]
PHST- 2006/01/07 09:00 [entrez]
AID - 12/1/264 [pii]
AID - 10.1158/1078-0432.CCR-05-1052 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2006 Jan 1;12(1):264-72. doi: 10.1158/1078-0432.CCR-05-1052.