Effects of a cyclooxygenase-1-selective inhibitor in a mouse model of ovarian cancer, administered alone or in combination with ibuprofen, a nonselective cyclooxygenase inhibitor.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to be potent inhibitors of the cyclooxygenases. The present study was designed to investigate the effects of a cyclooxygenase (COX)-1 inhibitor, SC-560, administered alone or in combination with ibuprofen on the growth inhibition of s.c. human ovarian SKOV-3 carcinoma and on angiogenesis. The effects of SC-560 and ibuprofen on tumor growth inhibition have been examined in mouse ovarian cancer models. Angiogenesis of both COX inhibitors was measured by reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Prostaglandin E(2) (PGE(2)) levels in tumor tissues of mice were also determined by ELISA. The inhibitory rates in SC-560 group alone and in combination with ibuprofen group were 21.21% and 41.55%, respectively. In combination therapy with SC-560 and ibuprofen, tumor volumes were significantly reduced compared with that of control group (P < 0.05). In treatment groups, both COX inhibitors significantly reduced intratumor PGE(2) levels (all P < 0.01). Microvessel density (MVD) in tumor tissues were significantly decreased from 80.90 +/- 5.14 in vehicle-treated to 40.70 +/- 10.45 and 38.90 +/- 8.41 in SC-560 group alone and combination ibuprofen therapy (all P < 0.01). Ibuprofen was similar to the cyclooxygenase-1-selective inhibitor SC-560 in its ability to suppress the values of MVD of tumor tissues. SC-560 administered alone or in combination with ibuprofen inhibited the COX-associated up-regulation of VEGF. These studies demonstrate synergism between two COX inhibitors and that antiangiogenic therapy can be used to inhibit ovarian cancer growth.
Li
Wei
W
Department of Gynecology and Obstetrics, Nanjing Medical University of Hangzhou Hospital, 310006, Hangzhou, China. wei5901482@tom.com
Xu
Ru-Jun
RJ
Lin
Zhen-Yun
ZY
Zhuo
Guang-Chao
GC
Zhang
Hong-He
HH
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; C115461:SC 560; D042461:Vascular Endothelial Growth Factor A; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D015232:Dinoprostone; D007052:Ibuprofen