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DIR Researchers Target Colorectal Cancer Prevention

By Eddy Ball
January 2007

In an NIEHS-funded study published in the November issue of Gastroenterology, DIR investigators working in the NIEHS Laboratory of Molecular Carcinogenesis (LMC) and Laboratory of Reproductive and Developmental Toxicology report on the anti-tumorigenic effects of over-expression of nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in transgenic mice. By elucidating the specific role of NAG-1 gene over-expression, the study's findings may have important consequences in the clinical setting. Colorectal cancer is one of the most common cancers and is responsible for the deaths of over 50,000 Americans each year.

The study's lead author, LMC Senior Investigator Thomas Eling, Ph.D., explained that investigators developed a transgenic mouse (NAG-Tg+) expressing the human form of a protein called NAG-1 to analyze the effect of the gene's expression in preventing intestinal tumor development in vivo. Researchers evaluated two colorectal carcinogenesis models in NAG-Tg+ mice to determine the efficacy of NAG-1 over-expression. They used a known intestinal carcinogen, azoxymethane, to induce tumors chemically and an intestinal tumor-specific genetic mutation (ApcMin+) to induce cancer genetically in NAG-Tg+ mice and controls. Both groups of NAG-Tg+ mice showed a greater than 50% reduction in intestinal cancer, confirming the tumor suppression activity of NAG-1.

The research team's result "demonstrates that expression of NAG-1 in vivo can suppress chemically induced carcinogenesis in the colon." Crossing the NAG-Tg+ mice with ApcMin+ mice resulted in a 60% reduction in polyp load compared to controls with genetic induction. The animals showed no apparent physical side effects other than a reduction in weight, especially in males.

The study built on previous in vitro findings. Results constitute the first confirmation of NAG-1 anti-tumorigenic effects in vivo and may lead to development of preventive agents that will not have the damaging cardiovascular and gastric side effects of cyclooxygenase (COX) inhibitors. Despite the efficacy of COX-1/-2 inhibitors in reducing risk of colorectal cancer, the side effects preclude their routine use.

This research adds to earlier work by Eling and several members of this research team demonstrating in vivo that a new experimental anticancer drug, Phortress, induces NAG-1 and significantly inhibits tumor growth.

The study was supported by NIH grants and the NIEHS Intramural Research Program.

For Eling's research team, this publication in Gastroenterology marks the recognition by the mainstream gastroenterological community of the clinical potential of stimulating NAG-1 expression by means other than COX-1/-2 inhibitors. The journal Gastroenterology is the official journal of the American Gastroenterology Association Institute and is widely considered to be the most prominent journal in the field of gastrointestinal disease. In 2005, Institute for Scientific Information Journal Citation Reports ranked the journal first out of 47 gastroenterology and hepatology titles and calculated its Impact Factor at 12.386.

Citation: Baek SJ, Okazaki R, Lee SH, Martinez J, Kim JS, Yamaguchi K, Mishina Y, Martin DW, Shoieb A, McEntee MF, Eling TE. 2006. Nonsteroidal anti-inflammatory drug activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia, Gastroenterology 131(5):1553-60.

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