Suppression of polypogenesis in a new mouse strain with a truncated ApcDelta474 by a novel COX-2 inhibitor, JTE-522

Abstract

Mutations of the adenomatous polyposis coli gene (Apc) have been implicated in the occurrence of sporadic colon cancer. Various Apc knockout strains of mice have been created to better understand the function of this gene. In the present study, using gene targeting, we disrupted the mouse Apc gene at the end of exon 10 to compare its effect with the effects of other types of Apc gene disruption, all of which are on exon 15. The mice expressed a mutant form of mRNA that encoded 474 amino acids instead of 2845 amino acids due to exon duplication. In addition, these Apc(Delta474) knockout mice developed intestinal and mammary tumors. Since the most severe cases of familial adenomatous polyposis are associated with mutations on exon 15, our mutation at exon 10 was expected to result in a mild phenotype. However, the number of polyps that our mice developed was similar to that of other Apc knockout mice such as Apc(Min) and Apc(1309) mice. Cyclooxygenase-2 (COX-2) has been implicated in colorectal carcinoma. Apc(Delta474) mice treated with JTE-522, a novel COX-2-selective inhibitor, showed a significantly reduced number of polyps. These results suggest that COX-2 plays an important role in polypogenesis and COX-2-selective inhibitors can be used as new preventive therapeutics against colorectal tumors.

Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers

“…Histological analysis of four of them (two Apc D14/ þ mice and two Apc Min/ þ mice) showed that these tumors were mammary adenoacanthomas (data not shown), in agreement with a previous report. 13 Furthermore, homozygosity for the Apc D14 mutation was not compatible with adult life. Apc D14/ þ males were mated with Apc D14/ þ females and the DNA from 46 newborn pups was examined for Apc status: 63% were heterozygous while 37% were wild-type, and no pups had the Apc D14/D14 genotype.…”

“…Despite this, their phenotypes differ: Apc D716/ þ mice have many polyps (more than 300 per mouse), while Apc Min/ þ , Apc D14/ þ and Apc D474/ þ mice have only 30-100 polyps. 10,11,13 However, the Apc D716 allele still contains the recombination selection cassette that could interfere with the transcription of the targeted allele. And the recombination that produced the Apc D474 allele leads to the duplication of exons 7-10 in the targeted allele.…”

“…The other mouse Apc models carrying different Apc germline mutation also result in a high incidence of adenomas in the small intestine. [11][12][13] The reason why the phenotypes of mice and men differ is presently unknown.…”

JTE‐522, a selective cyclooxygenase‐2 inhibitor, inhibits induction but not growth and invasion of 1,2‐dimethylhydrazine‐induced tubular adenocarcinomas of colon in rats

“…14,15 This compound also inhibited liver and lung metastases of colon cancer expressing COX-2 but lacked effect on those lacking COX-2 expression in the nude mouse xenograft model. 16,17 In chemically induced colon carcinogenesis, we have previously shown that JTE-522 inhibited the development of aberrant crypt foci (ACF), the putative precursors of both human and experimental colon cancer, 18,19 when administered throughout the study.…”

Colorectal Adenomas

“…This supporting evidence includes the observation that COX isoenzymes are overexpressed in colorectal adenomas and tumors (74 -82). Targeted deletion of the COX-2 gene prevents CRC in animals, and celecoxib as well as other selective COX-2 inhibitors (e.g., JTE-522, NS-398, the tricyclic methyl sulfone derivative MF tricyclic, nimesulide, and rofecoxib) are also effective in preclinical models (83)(84)(85)(86)(87)(88)(89)(90)(91) The Subpart H approval was based on a randomized, double-blind, placebo-controlled study of 83 FAP patients in which 400 mg twice daily celecoxib for 6 months significantly reduced adenoma number by 28% [P ϭ 0.003 compared with the 4.5% reduction with placebo (100)]. In addition, this celecoxib dose significantly reduced adenoma burden (the sum of adenoma diameters) by 30.7% (P ϭ 0.001 compared with the 4.9% reduction with placebo).…”