Suppressive effect of sulindac on branch duct-intraductal papillary mucinous neoplasms

Hayashi, Tsuyoshi; Ishiwatari, Hirotoshi; Ihara, Hidetoshi; Kawano, Yutaka; Miyanishi, Koji; Kobune, Masayoshi; Takimoto, Rishu; Sonoda, Tomoko; Takayama, Tetsuji; Kato, Junji; Niitsu, Yoshiro

doi:10.1007/s00535-009-0089-8

Cited by 11 publications

(8 citation statements)

References 22 publications

(24 reference statements)

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“…Neither DFMO nor P-S, even when combined, showed signs of toxicity, particularly gastrointestinal toxicity, a major limitation of conventional sulindac. Indeed, safety concerns have prompted efforts to devise chemopreventive protocols using the lowest possible dose of sulindac that maintains adequate efficacy, including the co-administration of a gastroprotective drug (24). Our results are consistent with previous work indicating the preclinical efficacy of P-S (9; 10).…”

Section: Discussionmentioning

confidence: 99%

Phospho-Sulindac (OXT-328) Combined with Difluoromethylornithine Prevents Colon Cancer in Mice

Mackenzie

Ouyang

Xie

et al. 2011

Cancer Prevention Research

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The nonsteroidal antiinflammatory drug (NSAID) sulindac and the ornithine decarboxylase (ODC) antagonist difluoromethylornithine (DFMO), individually and together, are effective inhibitors of colon carcinogenesis. However, chronic use of sulindac is associated with significant side effects. We evaluated the chemopreventive efficacy of phospho-sulindac (P-S, OXT-328), an apparently safe derivative of sulindac, together with DFMO, in HT-29 human colon cancer xenografts. Nude mice were divided into 4 groups: group 1 received vehicle (corn oil); group 2 received P-S (100 mg/kg/d) by oral gavage; group 3 received DFMO (2% in drinking water); and group 4 received P-S (100 mg/kg/d) by gavage plus DFMO (2% in drinking water) (P-S/DFMO). Eighteen days after implantation, compared to controls, tumor volume was inhibited 65.9% by P-S, 52.9% by DFMO and 70.9% by P-S/DFMO (p<0.01 for all). P-S/DFMO reduced cell proliferation 27.1% and increased apoptosis 38.9% compared to controls (p<0.05 for both). Compared to controls, P-S reduced the levels of thioredoxin-1 (Trx-1) and thioredoxin reductase (TrxR), whereas DFMO reduced polyamine content (putrescine and spermidine) and TrxR levels. Importantly, P-S/DFMO decreased putrescine and spermidine levels and the expression of Trx-1, TrxR, and cyclooxygenase (COX)-2. Of these molecular targets, TrxR most consistently correlated with tumor growth. Study results show that P-S/DFMO is an efficacious drug combination for colon cancer prevention, and also demonstrate the safety of P-S, which may overcome the limiting side effects of conventional sulindac. P-S/DFMO has an intricate mechanism of action extending beyond polyamines and including the thioredoxin system, an emerging regulator of chemoprevention. P-S/DFMO merits further evaluation.

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Section: Discussionmentioning

confidence: 99%

Phospho-Sulindac (OXT-328) Combined with Difluoromethylornithine Prevents Colon Cancer in Mice

Mackenzie

Ouyang

Xie

et al. 2011

Cancer Prevention Research

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“…Finally, is there a role for medical management of IPMNs, such as chemoprevention, which could potentially inhibit the progression of IPMNs? One study examined the effect of sulindac in a series of 22 patients with BT-IPMNs and found that branch duct diameter and mural nodule height were significantly reduced in the treatment group when compared to the non-treatment controls [56]. As yet, no large-scale or randomized controlled trials of chemopreventive agents in BT-IPMNs have been reported.…”

Section: Prevention and Chemoprevention Of Bt-ipmnsmentioning

confidence: 99%

Branch-Type Intraductal Papillary Mucinous Neoplasms: An Update

Garcea

Dennison

2011

Pancreatology

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“…25 Therefore, aspirin, a COX-2 inhibitor, was expected to have a chemopreventive effect on invasive IPMN and PC development. In a prospective non-randomized controlled trial that evaluated the suppressive effect of NSAIDs on BD-IPMN, 26 Hayashi et al found that NSAIDs reduced cyst growth and MN height, which is a known surrogate marker of PC development, but it did not reduce increasing MPD diameter. This discrepancy with our results may be due to the short observation period (18 months) in the Hayashi et al study.…”

Section: Discussionmentioning

confidence: 99%

Effect of low-dose aspirin use on pancreatic cancer development and morphological changes on imaging in IPMN: A long-term cohort study

Takasaki

Nagata

Imbe

et al. 2017

United European Gastroenterology Journal

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Background: Aspirin use may reduce the incidence of pancreatic cancer (PC), but no data are available regarding its chemopreventive effects on intraductal papillary mucinous neoplasm (IPMN). We aimed to determine whether low-dose aspirin (LDA) reduces PC development and morphological changes on imaging in IPMN patients. Methods: A cohort of 448 IPMN patients periodically followed up with imaging tests was analyzed. We used one-to-two propensity score matching to adjust for differences between an LDA group (n ¼ 63) and a non-LDA group (n ¼ 385). Outcomes included increasing cyst diameter, increasing main pancreatic duct (MPD) diameter, mural nodule (MN) appearance and PC development. Results: After matching, 63 LDA and 126 non-LDA patients were selected. During follow-up (median, 5.5 years), no significant differences were found in increasing cyst diameter, MN appearance, or PC development. However, there were significantly fewer cases of increasing MPD diameter in the LDA group (4.8% vs. 12.7%; p ¼ 0.02). After adjustment for age and sex, LDA still decreased the risk of increasing MPD diameter (hazard ratio, 0.17; p ¼ 0.02). Conclusion: Our results do not support a chemopreventive effect of LDA on PC development. However, LDA reduces further MPD dilation in IPMN patients.

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Suppressive effect of sulindac on branch duct-intraductal papillary mucinous neoplasms

Abstract: Although a larger scale randomized controlled study is needed in future, the present results suggest the promise of chemoprevention of carcinoma derived from BD-IPMNs by sulindac.

Cited by 11 publications

References 22 publications

Phospho-Sulindac (OXT-328) Combined with Difluoromethylornithine Prevents Colon Cancer in Mice

Phospho-Sulindac (OXT-328) Combined with Difluoromethylornithine Prevents Colon Cancer in Mice

Branch-Type Intraductal Papillary Mucinous Neoplasms: An Update

Effect of low-dose aspirin use on pancreatic cancer development and morphological changes on imaging in IPMN: A long-term cohort study

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