Ferrandina Gabriella, Ranelletti Franco O, Legge Francesco, Lauriola Libero, Salutari Vanda, Gessi Marco, Testa Antonia C, Werner Ulrike, Navarra Pierluigi, Tringali Giuseppe, Battaglia Alessandra, Scambia Giovanni
Department of Gynecology/Obstetrics, Catholic University of the Sacred Heart, 00168 Rome, Italy.
Clin Cancer Res. 2003 Oct 1;9(12):4324-31.
We investigated whether a short treatment with the cyclooxygenase-2 (COX-2) inhibitor celecoxib could modulate Ki67 antigen and the caspase cleavage product of keratin 18, recognized as a marker of early apoptosis. The activity of celecoxib on microvessel density (MVD) and angio-power Doppler sonography-derived indices of tumor vascularization was also assessed. Serum levels of squamous cell carcinoma antigen and the proliferative potential and subsets of peripheral T cells before and after celecoxib treatment were also analyzed.
Tumor biopsy specimens from 14 patients with cervical cancer were obtained at baseline and after 10 days of celecoxib treatment (400 mg twice daily). Tumor and stroma COX-2 expression, Ki67, apoptosis, and MVD were assessed by immunohistochemistry, whereas prostaglandin E(2) levels were measured by RIA.
At baseline, COX-2 integrated density values in tumor compartment ranged from 10.7 to 60.1 (median, 26.5) and were significantly higher than tumor COX-2 integrated density values after celecoxib treatment (range, 0.6-42.3; median, 12.6; P = 0.0043). The percentages of Ki67-positive tumor cells in pre-celecoxib cases ranged from 39.3 to 87.4 (median, 50.8) and were significantly higher than the percentage in the corresponding posttreatment samples (range, 27.7-83.8; median, 43.1; P = 0.0092). MVD values in pre-celecoxib biopsies ranged from 28.0 to 55.0 (median, 38.5) and were significantly higher than the corresponding values in posttreatment samples (range, 16.0-49.5; median; 27.6; P = 0.012). Also, prostaglandin E(2) levels showed a trend to be reduced after celecoxib treatment (range: 4.7-386.6 pg/mg wet tissue in pretreated cases versus 4.8-91.9 pg/mg wet tissue in posttreated cases (P = 0.092).
In cervical cancer, celecoxib treatment decreases tumor COX-2 expression and markers of proliferation and neoangiogenesis, while being uneffective on stroma COX-2 levels, thus suggesting that selective COX-2 inhibitors may be a promising strategy not only for chemopreventive approaches but also for therapeutic approaches in this neoplasia.
我们研究了环氧化酶-2（COX-2）抑制剂塞来昔布的短期治疗是否能调节Ki67抗原以及角蛋白18的半胱天冬酶裂解产物，后者被认为是早期凋亡的标志物。还评估了塞来昔布对微血管密度（MVD）以及血管能量多普勒超声得出的肿瘤血管生成指标的活性。同时分析了塞来昔布治疗前后血清鳞状细胞癌抗原水平、外周血T细胞的增殖潜能及亚群。
获取14例宫颈癌患者的肿瘤活检标本，分别在基线时以及塞来昔布治疗10天后（每日两次，每次400mg）。通过免疫组织化学评估肿瘤和基质中的COX-2表达、Ki67、凋亡及MVD，而前列腺素E2水平通过放射免疫分析法测定。
基线时，肿瘤组织中COX-2积分密度值范围为10.7至60.1（中位数为26.5），显著高于塞来昔布治疗后的肿瘤COX-2积分密度值（范围为0.6至42.3；中位数为12.6；P = 0.0043）。塞来昔布治疗前Ki67阳性肿瘤细胞百分比范围为39.3至87.4（中位数为50.8），显著高于相应治疗后样本中的百分比（范围为27.7至83.8；中位数为43.1；P = 0.0092）。塞来昔布治疗前活检标本中的MVD值范围为28.0至55.0（中位数为38.5），显著高于治疗后样本中的相应值（范围为16.0至49.5；中位数为27.6；P = 0.012）。此外，塞来昔布治疗后前列腺素E2水平呈下降趋势（治疗前病例中范围为4.7至386.6pg/mg湿组织，治疗后病例中为4.8至91.9pg/mg湿组织，P = 0.092）。
在宫颈癌中，塞来昔布治疗可降低肿瘤COX-2表达以及增殖和新生血管生成的标志物，而对基质COX-2水平无影响，因此表明选择性COX-2抑制剂不仅可能是化学预防方法的一种有前景的策略，而且在这种肿瘤的治疗方法中也可能具有前景。
