Department of Gastroenterology, Gachon Graduate School of Medicine, Gachon University of Medicine and Science, Incheon, South Korea.
Cancer Prev Res (Phila). 2010 Oct;3(10):1314-33. doi: 10.1158/1940-6207.CAPR-09-0272. Epub 2010 Aug 24.
The emergence of infliximab was an epochal event in the treatment of inflammatory bowel disease (IBD). Because colitis-associated cancers arose in the setting of chronic inflammation, during which "inflammation-dysplasia-carcinoma sequence" prevails and anti-inflammatory agents can prevent carcinogenesis, we hypothesized whether infliximab can prevent colitic cancer in animal models for which C57BL/6 mice were exposed to 15 cycles of dextran sulfate sodium (DSS), with each cycle consisting of 0.7% DSS for 1 week followed by sterilized water for 10 days. Infliximab (4 mg/kg i.v.) was given on the 1st, 3rd, and 7th weeks or 25th, 27th, and 31st weeks of cycle according to "step-up" versus "top-down" strategy. Molecular change about inflammation and carcinogenesis was compared between groups. Multiple colorectal tumors developed in 75% to 80% of control mice, whereas only 16.7% of mice treated with infliximab on the 1st, 3rd, and 7th weeks developed colon tumors. Significant decreases in tumor necrosis factor-α level, mast cell number, and the expression of inflammatory cytokines were observed in top-down strategy using infliximab. The expression and activity of matrix metalloproteinase-9 (MMP-9) and MMP-11 were significantly decreased in mice treated with infliximab accompanied with attenuated numbers of "β-catenin-accumulated crypts." In animal group where infliximab was administered at later stage of 25th, 27th, and 31st weeks, no reduction in tumorigenesis was noted. These biological effects of infliximab were further explored in in vitro experiment using Raw264.7 and Jurkat T cells. Conclusively, earlier and intensive therapy with infliximab should be considered for either mitigating clinical course or preventing ultimate development of colitic cancer in high-risk IBD patients.
英夫利昔单抗的出现是炎症性肠病（IBD）治疗史上的一个划时代的事件。由于结肠炎相关癌症是在慢性炎症的背景下发生的，在此期间“炎症-异型增生-癌序列”占主导地位，而抗炎药物可以预防癌变，因此我们假设英夫利昔单抗是否可以预防结肠炎动物模型中的结肠癌，在该模型中，C57BL/6 小鼠接受了 15 个周期的葡聚糖硫酸钠（DSS）暴露，每个周期包括 1 周的 0.7%DSS 和 10 天的无菌水。根据“逐步上升”与“自上而下”策略，在第 1、3 和 7 周或第 25、27 和 31 周时给予英夫利昔单抗（4mg/kg 静脉注射）。比较各组之间炎症和癌变的分子变化。在对照组中，75%至 80%的小鼠发展为多发性结直肠肿瘤，而仅接受第 1、3 和 7 周英夫利昔单抗治疗的小鼠中有 16.7%发生结肠肿瘤。在使用英夫利昔单抗的自上而下策略中，观察到肿瘤坏死因子-α水平、肥大细胞数量和炎症细胞因子表达显著降低。用英夫利昔单抗治疗的小鼠中基质金属蛋白酶-9（MMP-9）和 MMP-11 的表达和活性显著降低，同时“β-连环蛋白蓄积隐窝”的数量减少。在第 25、27 和 31 周时给予英夫利昔单抗的动物组中，未观察到肿瘤发生减少。在使用 Raw264.7 和 Jurkat T 细胞的体外实验中进一步探讨了英夫利昔单抗的这些生物学效应。总之，对于高危 IBD 患者，应考虑更早、更密集地使用英夫利昔单抗来减轻疾病进程或预防最终发生结肠炎相关的癌症。
