Boolbol S K, Dannenberg A J, Chadburn A, Martucci C, Guo X J, Ramonetti J T, Abreu-Goris M, Newmark H L, Lipkin M L, DeCosse J J, Bertagnolli M M
Strang Cancer Prevention Center, New York, 10021, USA.
Cancer Res. 1996 Jun 1;56(11):2556-60.
Inducible cyclooxygenase (Cox-2), also known as prostaglandin H synthase 2 (PGH-2) is a key enzyme in the formation of prostaglandins and thromboxanes. Cox-2 is the product of an immediate-early gene that is expressed in response to growth factors, tumor promoters, or cytokines. Overexpression of Cox-2 is associated with both human colon cancers and suppression of apoptosis in cultured epithelia] cells, an activity that is reversed by the nonsteroidal anti-inflammatory drug, sulindac sulfide. To address the relationship between Cox-2, apoptosis, and tumor development in vivo, we studied C57BL/6J-Min/+(Min) mice, a strain containing a fully penetrant dominant mutation in the Apc gene, leading to the development of gastrointestinal adenomas by 110 days of age. Min mice were fed AIN-76A chow diet and given sulindac (0.5 +/- 0.1 mg/day) in drinking water. Control Min mice and homozygous C57BL/6J-+/+ normal littermates lacking the Apc mutation (+/+) were fed AIN-76A diet and given tap water to drink. At 110 days of age, all mice were sacrificed, and their intestinal tracts were examined. Control Min mice had 11.9 +/- 7.8 tumors per mouse compared to 0.1 +/- 0.1 tumors for sulindac-treated Min mice. As expected, +/+ littermates had no macroscopic tumors. Examination of histologically normal-appearing small bowel from Min animals revealed increased amounts of Cox-2 and prostaglandin E(2) compared to +/+ littermates. Using two different in situ techniques, terminal transferase-mediated dUTP nick end labeling and a direct immunoperoxidase method, Min animals also demonstrated a 27-47% decrease in enterocyte apoptosis compared to +/+ animals. Treatment with sulindac not only inhibited tumor formation but decreased small bowel Cox-2 and prostaglandin E(2) to baseline and restored normal levels of apoptosis. These data suggest that overexpression of Cox-2 is associated with tumorigenesis in the gastrointestinal epithelium, and that both are inhibited by sulindac administration.
诱导型环氧化酶（Cox-2），也被称为前列腺素H合成酶2（PGH-2），是前列腺素和血栓素形成过程中的关键酶。Cox-2是一个立即早期基因的产物，该基因在生长因子、肿瘤启动子或细胞因子的作用下表达。Cox-2的过度表达与人结肠癌以及培养的上皮细胞中细胞凋亡的抑制相关，非甾体抗炎药舒林酸硫化物可逆转这种活性。为了研究Cox-2、细胞凋亡与体内肿瘤发生之间的关系，我们研究了C57BL/6J-Min/ +（Min）小鼠，该品系在Apc基因中含有一个完全显性的突变，导致在110日龄时出现胃肠道腺瘤。给Min小鼠喂食AIN-76A标准饲料，并在饮用水中给予舒林酸（0.5±0.1毫克/天）。对照Min小鼠和缺乏Apc突变的纯合C57BL/6J-+/ +正常同窝小鼠（+/ +）喂食AIN-76A饲料并给予自来水饮用。在110日龄时，处死所有小鼠并检查其肠道。对照Min小鼠每只小鼠有11.9±7.8个肿瘤，而舒林酸处理的Min小鼠每只小鼠有0.1±0.1个肿瘤。正如预期的那样，+/ +同窝小鼠没有肉眼可见的肿瘤。对Min动物组织学外观正常的小肠检查发现，与+/ +同窝小鼠相比，Cox-2和前列腺素E（2）的含量增加。使用两种不同的原位技术，即末端转移酶介导的dUTP缺口末端标记和直接免疫过氧化物酶方法，与+/ +动物相比，Min动物的肠上皮细胞凋亡也减少了27 - 47％。舒林酸治疗不仅抑制肿瘤形成，还将小肠Cox-2和前列腺素E（2）降低至基线水平，并恢复正常的细胞凋亡水平。这些数据表明，Cox-2的过度表达与胃肠道上皮的肿瘤发生相关，并且两者都受到舒林酸给药的抑制。
