Prevention of colitis-associated carcinogenesis with infliximab.
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.
Kim
Yoon Jae
YJ
Department of Gastroenterology, Gachon Graduate School of Medicine, Gachon University of Medicine and Science, Incheon, South Korea.
Hong
Kyung Sook
KS
Chung
Jun Won
JW
Kim
Ju Hyun
JH
Hahm
Ki Baik
KB
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000150:complications / Q000378:metabolism; D000069285:Infliximab; D019169:Jurkat Cells; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016207:Cytokines; D016264:Dextran Sulfate; D000069285:Infliximab; D020782:Matrix Metalloproteinases