Reference SummaryMahmoud NN, Carcinogenesis 1998 Jan;19(1):87-91

Title

The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis.

Authors

Mahmoud NN; Boolbol SK; Dannenberg AJ; Mestre JR; Bilinski RT; Martucci C; Newmark HL; Chadburn A; Bertagnolli MM

Journal

Carcinogenesis

Volume

Issue

Year

1998

Pages

87-91

Abstract

Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is effective in treating intestinal adenomas in humans with Familial Adenomatous Polyposis (FAP) and in preventing intestinal tumors in the C57Bl/6J-Min+ (Min) mouse, an animal model of FAP. Sulindac is a prodrug metabolized by the liver and intestinal flora to a sulfone, which has no anti-inflammatory activity, and a sulfide, which is the active anti-inflammatory metabolite. In this study, we determined which of these metabolites is responsible for the anti-tumor effect of sulindac in Min mice. Min mice were treated with either sulindac sulfone or sulindac sulfide (0.5 +/- 0.1 mg/day). Min mice and homozygous C57Bl/6J-(+/+) normal litter-mates lacking the Apc mutation (+/+) were used as controls. At 110 days of age, all mice were euthanized and their intestinal tracts examined. Control Min mice had 33.2 +/- 6.6 tumors per mouse compared to 0.6 +/- 0.3 tumors for sulindac sulfide- treated Min mice (P < 0.001) and 21.9 +/- 4.5 tumors per mouse for sulindac sulfone-treated Min mice (P > 0.05). Decreased enterocyte apoptosis was observed in Min control mice and Min mice treated with sulindac sulfone. Sulindac sulfide restored to normal the level of apoptosis in the mucosa of Min animals and decreased levels of PGE2 in the small intestine of treated Min animals by 59% (P < 0.001). These data suggest that the anti-tumor effect of sulindac in Apc-deficient animals is mediated by the sulfide metabolite and correlates with suppression of tissue prostaglandin synthesis.

Links

J:45638 – MGI References
9472698 – National Library of Medicine/PubMed

Strain Notes

Strain	Note
C57BL/6J-Apc^Min/+	These mice were from The Jackson Laboratory.

Models
Strain	Model Name	Treatment Agent(s)	Organ Affected	Frequency
C57BL/6J-Apc^Min/+	Intestine adenoma		Intestine	100
C57BL/6J-Apc^Min/+	Intestine adenoma	sulindac sulfide	Intestine	30
C57BL/6J-Apc^Min/+	Intestine adenoma	sulindac sulfone	Intestine	100
C57BL/6J	Intestine adenoma		Intestine	0