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.

ABSTRACT

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.