Cyclo-oxygenase inhibition reduces tumour growth and metastasis in an orthotopic model of breast cancer.
The effect of selective and non-selective cyclo-oxygenase inhibition on tumour growth and metastasis in an orthotopic model of breast cancer was investigated. 4T1 mammary adenocarcinoma cells were injected into the mammary fat pad of female BALB/c mice. When tumours reached a mean tumour diameter of 8.4+/-0.4 mm, mice were randomised into three groups (n=6 per group) and received daily intraperitoneal injections of the selective cyclo-oxygenase-2 inhibitor, SC-236, the non selective cyclo-oxygenase inhibitor, Indomethacin, or drug vehicle. Tumour diameter was recorded on alternate days. From 8 days after initiation of treatment, tumour diameter in animals treated with either SC-236 or indomethacin was significantly reduced relative to controls. Both primary tumour weight and the number of lung metastases were significantly reduced in the SC-236 and indomethacin treated mice. Microvessel density was reduced and tumor cell apoptosis increased in the primary tumour of mice treated with either the selective or non-selective cyclo-oxygenase inhibitor. In vitro, cyclo-oxygenase inhibition decreased vascular endothelial growth factor production and increased apoptosis of tumour cells. Our results suggest that cyclo-oxygenase inhibitors will be of value in the treatment of both primary and metastatic breast cancer.
Connolly
E M
EM
Department of Surgery, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
Harmey
J H
JH
O'Grady
T
T
Foley
D
D
Roche-Nagle
G
G
Kay
E
E
Bouchier-Hayes
D J
DJ
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control / Q000556:secondary*; D008222:Lymphokines / Q000096:biosynthesis; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000637:transplantation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000096926:Benzenesulfonamides
D020533:Angiogenesis Inhibitors; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016228:Endothelial Growth Factors; D007213:Indomethacin; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C496512:Ptgs1 protein, mouse