Kanwar Shailender S, Vaiphei Kim, Nehru Bimla, Sanyal Sankar N
Department of Biophysics, Panjab University, Chandigarh- 160 014, India.
J Environ Pathol Toxicol Oncol. 2008;27(2):89-100. doi: 10.1615/jenvironpatholtoxicoloncol.v27.i2.20.
The role of nonsteroidal anti-inflammatory drugs (NSAIDs) was studied on the antioxidant defense system and nitric oxide-derived damage in a 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Early precancerous lesions were established in the proximal and distal regions of the colon by morphological and histopathological examinations that were greatly regressed by the simultaneous treatment of the three NSAIDs, such as aspirin, celecoxib, and etoricoxib, along with the procarcinogen DMH. The intestinal brush border membrane (BBM) was isolated from the two regions and the colon-specific marker enzyme cysteine-sensitive alkaline phosphatase was assayed, which showed considerable elevation by DMH but reverted back to normal level by all the three NSAIDs. DMH also caused a higher level of lipid peroxidation as measured by malonyldialdehyde production, which was also found to be corrected by the NSAIDs, in both the region of the colonic tissue. The antioxidant activities were further established by a higher level of superoxide dismutase, catalase, glutathione reductase, and glutathione S-transferase in the NSAID treatment as compared to the DMH. The nonenzyme tripeptide, glutathione content was also recovered similarly as an antioxidant defense mechanism. To elucidate whether nitric oxide (NO) also plays an important role in the pathophysiology of colon cancer, the NO and citrulline levels were measured. The results show that the NO was lowered in DMH treatment and elevated by the administration of the NSAIDs while the citrulline level could not be recovered back. The findings of the present investigation indicate the chemopreventive modalities of the NSAIDs, particularly the COX-2 inhibitors.
研究了非甾体抗炎药（NSAIDs）对1,2-二甲基肼（DMH）诱导的大鼠结肠癌发生过程中抗氧化防御系统和一氧化氮衍生损伤的作用。通过形态学和组织病理学检查在结肠近端和远端区域建立早期癌前病变，同时给予三种NSAIDs（如阿司匹林、塞来昔布和依托考昔）与致癌物前体DMH共同处理，可使这些病变显著消退。从这两个区域分离出肠刷状缘膜（BBM），并检测结肠特异性标记酶半胱氨酸敏感碱性磷酸酶，结果显示DMH使其显著升高，但三种NSAIDs均可使其恢复至正常水平。通过丙二醛生成量测定发现，DMH还导致结肠组织两个区域的脂质过氧化水平升高，而NSAIDs也可纠正这一现象。与DMH组相比，NSAIDs处理组中超氧化物歧化酶、过氧化氢酶、谷胱甘肽还原酶和谷胱甘肽S-转移酶水平更高，进一步证实了其抗氧化活性。非酶三肽谷胱甘肽含量也作为一种抗氧化防御机制类似地得到恢复。为阐明一氧化氮（NO）是否也在结肠癌的病理生理学中起重要作用，检测了NO和瓜氨酸水平。结果表明，DMH处理组中NO水平降低，而给予NSAIDs后升高，同时瓜氨酸水平未能恢复。本研究结果表明NSAIDs具有化学预防作用，尤其是COX-2抑制剂。
