Li Wei, Zhang Hong-he, Xu Ru-jun, Zhuo Guang-chao, Hu Ye-qing, Li Juan
Department of Gynecology and Obstetrics, Nanjing Medical University of Hangzhou Hospital, Hangzhou 310006, PR China.
Med Oncol. 2008;25(2):172-7. doi: 10.1007/s12032-007-9016-0. Epub 2007 Oct 6.
New therapies against cancer are based on targeting cyclooxygenase-2 (COX-2). Whether COX-2 inhibitor therapy would be beneficial in the prevention and/or treatment of ovarian cancer still remains unclear. This study was designed to investigate whether nimesulide, a COX-2 selective inhibitor, could suppress tumor growth in implanted ovarian carcinoma mice and to explore the molecular mechanisms. Human ovarian SKOV-3 carcinoma cells xenograft-bearing mice were treated with nimesulide 62.5 mg/kg or 250 mg/kg alone i.g., daily for 21 days. Microvessel density (MVD) of ovarian carcinoma was determined with anti-CD(34) as the label. Prostaglandin E2 (PGE2) levels were also determined by ELISA. In addition, the expression of COX-2 and COX-1 at protein and mRNA levels in the control groups was also detected by immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR). Nimesulide treatment showed a dose-dependent growth-inhibitory effect of human ovarian SKOV-3 tumors. The inhibitory rates in nimesulide 62.5 mg/kg group and 250 mg/kg group were 20.40% and 50.55% respectively, however, which is not significant statistically compared with that of control group (P > 0.05). In treatment groups, nimesulide significantly reduced intratumor PGE2 levels (all, P < 0.01). Microvessel densities in treatment groups were 61.20 +/- 1.67 (62.5 mg/kg) and 66.27 +/- 1.20 (250 mg/kg), which are significant statistically compared with that of control group (79.97 +/- 1.07) (all, P < 0.01). However, COX-1, not COX-2, mRNA, and protein levels are elevated in tumor tissues. Nimesulide decreased microvessel density is associated with the reduction of PGE2 levels but without affecting growth inhibition and the expression of COX-2. Importantly, tumor growth implanted in SKOV-3 mice was not significantly attenuated suggesting that COX-1 in ovarian carcinoma tissue also has an important role in tumor growth. These findings may implicate COX-1 as a suitable target for the treatment of ovarian cancer.
新型抗癌疗法基于靶向环氧化酶-2（COX-2）。COX-2抑制剂疗法在预防和/或治疗卵巢癌中是否有益仍不清楚。本研究旨在调查COX-2选择性抑制剂尼美舒利是否能抑制植入卵巢癌小鼠的肿瘤生长，并探索其分子机制。将荷有人卵巢SKOV-3癌细胞异种移植物的小鼠单独给予62.5mg/kg或250mg/kg尼美舒利，经口给药，每日一次，共21天。以抗CD(34)为标记物测定卵巢癌的微血管密度（MVD）。还通过酶联免疫吸附测定法（ELISA）测定前列腺素E2（PGE2）水平。此外，通过免疫组织化学和逆转录聚合酶链反应（RT-PCR）检测对照组中COX-2和COX-1在蛋白质和mRNA水平的表达。尼美舒利治疗显示出对人卵巢SKOV-3肿瘤的剂量依赖性生长抑制作用。尼美舒利62.5mg/kg组和250mg/kg组的抑制率分别为20.40%和50.55%，然而，与对照组相比，差异无统计学意义（P>0.05）。在治疗组中，尼美舒利显著降低肿瘤内PGE2水平（均P<0.01）。治疗组的微血管密度分别为61.20±1.67（62.5mg/kg）和66.27±1.20（250mg/kg），与对照组（79.97±1.07）相比，差异有统计学意义（均P<0.01）。然而，肿瘤组织中COX-1的mRNA和蛋白质水平升高，而非COX-2。尼美舒利降低微血管密度与PGE2水平降低有关，但不影响生长抑制和COX-2的表达。重要的是，植入SKOV-3小鼠的肿瘤生长未显著减弱，这表明卵巢癌组织中的COX-1在肿瘤生长中也起重要作用。这些发现可能表明COX-1是治疗卵巢癌的合适靶点。
