Department of Biophysics, Panjab University, Chandigarh - 160 014, India.
J Environ Pathol Toxicol Oncol. 2010;29(1):41-53. doi: 10.1615/jenvironpatholtoxicoloncol.v29.i1.70.
We evaluated the role of diclofenac, a dual cycloxygenase inhibitor, in chemoprevention of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rat model. In a six-week long treatment with DMH (initiation stage), colonic mucosa showed a rich presence of preneoplastic lesions, such as multiple plaque lesions (MPL), aberrant crypt foci (ACF), and histologically well-characterized dysplasia. Control animals were free from these features while simultaneous treatment of DMH and diclofenac resulted in a significant reduction of these. The Diclofenac-only group did not show any prominent carcinogenic feature. The colonic tissue showed increased COX-2 expression in the DMH group, immunohistochemically and by western blotting. Apoptosis was quantified in isolated colonocytes by fluorescent staining and by TUNEL assay in tissue sections. The number of apoptotic cells was few in the DMH group, while it was featured prominently in all the other groups. The dose of the diclofenac used in the present study was established at an anti-inflammatory dose by the carrageenan-induced rodent paw oedema test. Because ACF can be accepted as reliable prognostic biomarkers in colon carcinogenesis, its inhibition and also the induction of the apoptosis process may favorably indicate the preclinical promise for chemoprevention of colon cancer as demonstrated in the initiation phase of carcinogenesis.
我们评估了双环氧化酶抑制剂双氯芬酸在预防 1,2-二甲基肼（DMH）诱导的大鼠结肠癌发生中的作用。在为期六周的 DMH（启动阶段）治疗中，结肠黏膜显示出丰富的癌前病变，如多发性斑块病变（MPL）、异常隐窝病灶（ACF）和组织学上特征明确的发育不良。对照动物没有这些特征，而同时给予 DMH 和双氯芬酸治疗则显著减少了这些病变。单独给予双氯芬酸组没有表现出任何明显的致癌特征。DMH 组的结肠组织 COX-2 表达增加，免疫组织化学和 Western blot 均证实了这一点。通过荧光染色和组织切片的 TUNEL 测定，定量分离的结肠细胞中的凋亡。在 DMH 组中，凋亡细胞的数量很少，而在所有其他组中则很明显。本研究中使用的双氯芬酸剂量通过角叉菜胶诱导的啮齿动物爪肿胀试验确定为抗炎剂量。因为 ACF 可以被接受为结肠癌发生中可靠的预后生物标志物，其抑制和凋亡过程的诱导可能有利地表明在癌症发生的启动阶段，对结肠癌的化学预防具有临床前前景。
