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Intermittent Dosing with Sulindac Provides Effective Colorectal Cancer Chemoprevention in the Azoxymethane-Treated Mouse Model.

ABSTRACT: Sulindac is an NSAID that can provide effective chemoprevention for colorectal cancer. In this study, alternative dosing regimens of sulindac were evaluated for their chemoprevention effectiveness in the azoxymethane-treated A/J mouse model of colorectal cancer. High-resolution endoscopic optical coherence tomography was utilized to time-serially measure tumor number and tumor burden in the distal colon as the biological endpoints. Four treatment groups were studied: (i) daily for 20 weeks (sulindac-daily); (ii) for 2 weeks, then no sulindac for 2 weeks, cycle repeated 5 times (sulindac-2); (iii) for 10 weeks ("on"), then no sulindac for 10 weeks ("off"; sulindac-10); and (iv) no sulindac (sulindac-none). Sulindac-2 and sulindac-daily had statistically significantly lower final tumor counts and slopes (change in number of tumors per week) when compared with sulindac-none (P < 0.0001). All of the treatment groups had statistically significantly lower final tumor burdens and slopes when compared with sulindac-none (P < 0.001). There was a prolonged latency period in the sulindac-10 group, with no significant difference between the "off" portion of this treatment and sulindac-none. These results suggest that, although daily doses of sulindac provide the most optimal effects, intermittent doses of sulindac in a 50% duty cycle with an overall 4-week period (sulindac-2 model) can provide highly effective chemoprevention of colorectal cancer in this model. After cessation of sulindac treatment (sulindac-10 "off"), there is no evidence of either a persistent chemopreventive effect or a rebound effect. Cancer Prev Res; 10(8); 459-66. ©2017 AACR.

SUBMITTER: Chandra S

PROVIDER: S-EPMC5544532 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Intermittent Dosing with Sulindac Provides Effective Colorectal Cancer Chemoprevention in the Azoxymethane-Treated Mouse Model.

Chandra Swati S Nymeyer Ariel C AC Rice Photini Faith PF Gerner Eugene W EW Barton Jennifer K JK

Cancer prevention research (Philadelphia, Pa.) 20170613 8

Sulindac is an NSAID that can provide effective chemoprevention for colorectal cancer. In this study, alternative dosing regimens of sulindac were evaluated for their chemoprevention effectiveness in the azoxymethane-treated A/J mouse model of colorectal cancer. High-resolution endoscopic optical coherence tomography was utilized to time-serially measure tumor number and tumor burden in the distal colon as the biological endpoints. Four treatment groups were studied: (i) daily for 20 weeks (suli ...[more]

PMID: 28611038

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Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are promising colorectal cancer (CRC) chemopreventive drugs; however, to overcome NSAIDs' associated side effects, there is a need to develop safer and efficacious approaches. The present study was designed to evaluate (i) the efficacy of nitric-oxide releasing (NO)-Sulindac as compared to Sulindac; (ii) whether NO-Sulindac is superior to Sulindac in enhancing low-dose difluoromethylornithine (DFMO)-induced chemopreventive efficacy, and (iii) assessing the key biomarkers associated with colon tumor inhibition by these combinations. In F344 rats, colonic tumors were induced by azoxymethane (AOM). At the adenoma stage (13 weeks post AOM), groups of rats were fed the experimental diets containing 0 ppm, 500 ppm DFMO, 150 ppm Sulindac, and 200 ppm NO-Sulindac, individually or in combinations, for 36 weeks. Colon tumors were evaluated histopathologically and assayed for expression levels of proliferative, apoptotic, and inflammatory markers. Results suggest that (except for NO-Sulindac alone), DFMO, Sulindac individually, and DFMO combined with Sulindac or NO-Sulindac significantly suppressed AOM-induced adenocarcinoma incidence and multiplicities. DFMO and Sulindac suppressed adenocarcinoma multiplicity by 63% (p < 0.0001) and 51% (p < 0.0011), respectively, whereas NO-Sulindac had a modest effect (22.8%, p = 0.09). Combinations of DFMO plus Sulindac or NO-Sulindac suppressed adenocarcinoma incidence (60%, p < 0.0001; 50% p < 0.0004), and multiplicity (81%, p < 0.0001; 62%, p < 0.0001). Rats that were fed the combination of DFMO plus Sulindac showed significant inhibition of tumor cell proliferation and induction of apoptosis. In addition, enhancement of p21, Bax, and caspases; downregulation of Ki-67, VEGF, and β-catenin; and modulation of iNOS, COX-2, and ODC activities in colonic tumors were observed. These observations show that a lower-dose of DFMO and Sulindac significantly enhanced CRC chemopreventive efficacy when compared to NO-Sulindac alone, and the combination of DFMO and NO-Sulindac was modestly efficacious as compared to DFMO alone.

Project description:BackgroundChronic inflammation is well known to be a risk factor for colon cancer. Previously we established a novel mouse model of inflammation-related colon carcinogenesis, which is useful to examine the involvement of inflammation in colon carcinogenesis. To shed light on the alterations in global gene expression in the background of inflammation-related colon cancer and gain further insights into the molecular mechanisms underlying inflammation-related colon carcinogenesis, we conducted a comprehensive DNA microarray analysis using our model.MethodsMale ICR mice were given a single ip injection of azoxymethane (AOM, 10 mg/kg body weight), followed by the addition of 2% (w/v) dextran sodium sulfate (DSS) to their drinking water for 7 days, starting 1 week after the AOM injection. We performed DNA microarray analysis (Affymetrix GeneChip) on non-tumorous mucosa obtained from mice that received AOM/DSS, AOM alone, and DSS alone, and untreated mice at wks 5 and 10.ResultsMarkedly up-regulated genes in the colonic mucosa given AOM/DSS at wk 5 or 10 included Wnt inhibitory factor 1 (Wif1, 48.5-fold increase at wk 5 and 5.7-fold increase at wk 10) and plasminogen activator, tissue (Plat, 48.5-fold increase at wk 5), myelocytomatosis oncogene (Myc, 3.0-fold increase at wk 5), and phospholipase A2, group IIA (platelets, synovial fluid) (Plscr2, 8.0-fold increase at wk 10). The notable down-regulated genes in the colonic mucosa of mice treated with AOM/DSS were the peroxisome proliferator activated receptor binding protein (Pparbp, 0.06-fold decrease at wk 10) and the transforming growth factor, beta 3 (Tgfb3, 0.14-fold decrease at wk 10). The inflammation-related gene, peroxisome proliferator activated receptor gamma (Ppargamma 0.38-fold decrease at wk 5), was also down-regulated in the colonic mucosa of mice that received AOM/DSS.ConclusionThis is the first report describing global gene expression analysis of an AOM/DSS-induced mouse colon carcinogenesis model, and our findings provide new insights into the mechanisms of inflammation-related colon carcinogenesis and the establishment of novel therapies and preventative strategies against carcinogenesis.

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Intermittent Dosing with Sulindac Provides Effective Colorectal Cancer Chemoprevention in the Azoxymethane-Treated Mouse Model.

Publications

Intermittent Dosing with Sulindac Provides Effective Colorectal Cancer Chemoprevention in the Azoxymethane-Treated Mouse Model.

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