Sulindac for polyposis of the colon

Waddell, William R.; Ganser, Gary F.; Cerise, Elmo J.; Loughry, R W

doi:10.1016/0002-9610(89)90442-x

Cited by 411 publications

(194 citation statements)

References 30 publications

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“…This suggests that multiple apoptotic controls exist to control neoplasia in long-lived organisms such as the human. In colorectal mucosa, the first apoptotic control point appears to be mediated by APC, while a reserve system, (38)(39)(40)(41)(42). Because colorectal tumor cells lack intact APC, it was suggested that these NSAIDs replace a physiologic function of APC that was abrogated by mutation.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis and APC in colorectal tumorigenesis.

Morin

Vogelstein²,

Kinzler³

1996

Proc. Natl. Acad. Sci. U.S.A.

433

326

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Tumors result from disruptions in the homeostatic mechanisms that regulate cell birth and cell death. In colon cancer, one of the earliest manifestation of this imbalance is the formation of polyps, caused by somatic and inherited mutations of the adenomatous polyposis coli (APC) tumor suppressor gene in both humans and mice. While the importance of APC in tumorigenesis is well documented, how it functions to prevent tumors remains a mystery. Using a novel inducible expression system, we show that expression of APC in human colorectal cancer cells containing endogenous inactive APC alleles results in a substantial diminution of cell growth. Further evaluation demonstrated that this was due to the induction of cell death through apoptosis. These results suggest that apoptosis plays a role not only in advanced tumors but also at the very earliest stages of neoplasia.

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Section: Discussionmentioning

confidence: 99%

Apoptosis and APC in colorectal tumorigenesis.

Morin

Vogelstein²,

Kinzler³

1996

Proc. Natl. Acad. Sci. U.S.A.

433

326

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“…A large fraction of sulindac is converted to sulindac sulfide in the colon by colonic bacteria (32). Therefore, high lumenal concentrations of sulindac sulfide are achieved in the colon (33). In addition, animal studies have shown that sulindac sulfide is concentrated in the mucosa of the colon at levels several-fold higher than in the serum (34).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, animal studies have shown that sulindac sulfide is concentrated in the mucosa of the colon at levels several-fold higher than in the serum (34). Colonic epithelial cells can be exposed to concentrations up to 20-fold higher than those in serum (33); serum levels of sulindac sulfide are about [10][11][12][13][14][15] MM when sulindac is given orally at doses which regress polyps in FAP patients (35,36). Sulindac, was used at concentrations several times higher than sulindac sulfide to see if the parent compound could mimic its effects.…”

Section: Introductionmentioning

confidence: 99%

Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells.

Shiff¹,

Qiao²,

Tsai³

et al. 1995

J. Clin. Invest.

370

204

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Nonsteroidal antlinflammatory drugs (NSAIDs), have cancer preventive and tumor regressive effects in the human colon. They lower the incidence of and mortality from colorectal cancer and sulindac reduces the number and size of polyps in patients with familial adenomatous polyposis.We studied the effect of sulindac, and its metabolite sulindac sulfide, on the proliferation of HT-29 colon adenocarcinoma cells. Both compounds reduced the proliferation rate of these cells, changed their morphology, and caused them to accumulate in the Go/Gj phase of the cell cycle. These responses were time-and concentration-dependent and reversible. In addition, these compounds reduced the level and activity of several cyclin-dependent kinases (cdks), which regulate cell cycle progression. Sulindac and sulindac sulfide also induced apoptosis in these cells at concentrations that affected their proliferation, morphology, and cell cycle phase distribution. Sulindac sulfide was approximately sixfold more potent than sulindac in inducing these cellular responses.Our results indicate that inhibition of cell cycle progression and induction of apoptotic cell death contribute to the anti-proliferative effects of sulindac and sulindac sulfide in HT-29 cells. These findings may be relevant to the cancer preventive and tumor regressive effects of these compounds in humans. (J. Clin. Invest. 1995. 96:491-503.)

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“…Oncogene (2005) ; methylation Sulindac, a nonsteoridal anti-inflammatory drug (NSAID), has considerable activity as a chemopreventive agent for human colon cancer (Waddell et al, 1989;Labayle et al, 1991;Giardiello et al, 1993;Nugent et al, 1993). The activity of sulindac in inhibition of intestinal tumorigenesis is recapitulated in mouse models in which tumors are initiated by the targeting of the Apc gene (Boolbol et al, 1996;Yang et al, 2001b).…”

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confidence: 99%