Time-serial Assessment of Drug Combination Interventions in a Mouse Model of Colorectal Carcinogenesis Using Optical Coherence Tomography

LeGendre-McGhee, Susan; Rice, Photini F. S.; Wall, R. Andrew; Sprute, Kyle J.; Bommireddy, Ramireddy; Luttman, Amber M.; Nagle, Raymond B.; Abril, Edward R.; Farrell, Katrina; Hsu, Chiu‐Hsieh; Roe, Denise J.; Gerner, Eugene W.; Ignatenko, Natalia A.; Barton, Jennifer K.

doi:10.4137/cgm.s21216

Cited by 4 publications

(13 citation statements)

References 64 publications

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“…However, in this study OCT frequently underestimated the number and burden of adenoma, leading to a sensitivity of only 68%. This finding is lower than our previous studies, one of which identified adenoma with a sensitivity of 89% (3) and another which identified adenoma with a sensitivity of 95% (23). OCT was highly specific with only 1 false positive obtained in the study.…”

Section: Discussioncontrasting

confidence: 92%

“…Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) that is proven to be an effective chemopreventive agent for CRC in mouse models (3, 4) and human clinical trials (4–6) Sulindac acts via cyclooxygenase-dependent mechanisms by inhibiting the activity of both cyclooxygenase-1 and −2 (COX-1/COX-2), enzymes implicated in tumor formation in colorectal carcinogenesis (4, 7), as well as cyclooxygenase-independent ways (8). NSAIDs and inhibitors of polyamine synthesis have been proven to suppress AOM-induced colon carcinogenesis (9).…”

Section: Introductionmentioning

confidence: 99%

“…Sulindac activates polyamine catabolism and export by a cyclooxygenase independent mechanism (10) and sulindac suppression of intestinal adenomas in the Apc Min/+ mouse is polyamine dependent (11). It has been shown to act in both the initiation and promotion stages of colorectal carcinogenesis, and it has been demonstrated to reduce the increase in number of tumors if administered following the appearance of adenomas in the colon in the mouse (3). …”

Section: Introductionmentioning

confidence: 99%

“…Optical coherence tomography ChaOCT) is a high resolution, rapid imaging technology that uses near-infrared light to create cross-sectional images in scattering media like colon tissue (23). It is both minimally invasive and non-destructive, and it has previously been shown to rapidly and accurately detect adenomas and monitor disease progression in the mouse colon (3). …”

Section: Introductionmentioning

confidence: 99%

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

Chandra

Nymeyer

Rice

et al. 2017

Cancer Prevention Research

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Sulindac is a nonsteroidal anti-inflammatory drug 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: 1) daily for 20 weeks (Sulindac-Daily), 2) for two weeks, then no sulindac for two weeks, cycle repeated 5 times (Sulindac-2), 3) for ten weeks (“on”), then no sulindac for 10 weeks (“off”) (Sulindac-10), 4) 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, while daily doses of sulindac provide the most optimal effects, intermittent doses of sulindac in a 50% duty cycle with an overall four-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 not evidence of either a persistent chemopreventive effect nor a rebound effect.

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Section: Discussioncontrasting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Chandra

Nymeyer

Rice

et al. 2017

Cancer Prevention Research

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“…The H&E-stained sections of the colons of all animals were analyzed by an independent observer for tumor number and burden. Tumors were counted and volume was determined by measuring the maximum diameter of each discrete tumor using the Olympus Microsuite FIVE (2007) software, and assuming a spherical tumor, as described previously (30). A comparison of final time point OCT-and histology-determined tumor number and burden was made.…”

Section: Tissue Collection and Histologymentioning

confidence: 99%

Does Mutated K-RAS Oncogene Attenuate the Effect of Sulindac in Colon Cancer Chemoprevention?

Rice

Ehrichs

Jones

et al. 2018

Cancer Prevention Research

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The NSAID sulindac has been successfully used alone or in combination with other agents to suppress colon tumorigenesis in patients with genetic predisposition and also showed its efficacy in prevention of sporadic colon adenomas. At the same time, some experimental and clinical reports suggest that a mutant oncogene may negate sulindac antitumor efficacy. To directly assess sulindac activity at suppressing premalignant lesions carrying K-RAS mutation, we utilized a novel mouse model with an inducible colon-specific expression of the mutant oncogene ( ). Tumor development and treatment effects were monitored by minimally invasive endoscopic Optical coherence tomography. Expression of the mutant allele accelerated azoxymethane (AOM)-induced colon carcinogenesis in C57BL/6 mice, a strain otherwise resistant to this carcinogen. Sulindac completely prevented AOM-induced tumor formation in wild-type ( wt) animals. In -mutant mice, a 38% reduction in tumor number, an 83% reduction in tumor volume ( ≤ 0.01) and an increase in the number of adenoma-free mice ( = 0.04) were observed. The partial response of animals to sulindac treatment was evident by the decrease in mucosal thickness ( < 0.01) and delay in progression of the precancerous aberrant crypt foci to adenomas. Molecular analyses showed significant induction in cyclooxygenase 2 (COX-2), cleaved caspase-3 (CC3), and Ki-67 expression by AOM, but not sulindac treatment, in all genotypes. Our data underscore the importance of screening for mutations in individuals with colon polyps to provide more personalized interventions targeting mutant signaling pathways. .

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Alpha-Difluoromethylornithine, an Irreversible Inhibitor of Polyamine Biosynthesis, as a Therapeutic Strategy against Hyperproliferative and Infectious Diseases

LoGiudice

Abuan

et al. 2018

Medical Sciences

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The fluorinated ornithine analog α-difluoromethylornithine (DFMO, eflornithine, ornidyl) is an irreversible suicide inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme of polyamine biosynthesis. The ubiquitous and essential polyamines have many functions, but are primarily important for rapidly proliferating cells. Thus, ODC is potentially a drug target for any disease state where rapid growth is a key process leading to pathology. The compound was originally discovered as an anticancer drug, but its effectiveness was disappointing. However, DFMO was successfully developed to treat African sleeping sickness and is currently one of few clinically used drugs to combat this neglected tropical disease. The other Food and Drug Administration (FDA) approved application for DFMO is as an active ingredient in the hair removal cream Vaniqa. In recent years, renewed interest in DFMO for hyperproliferative diseases has led to increased research and promising preclinical and clinical trials. This review explores the use of DFMO for the treatment of African sleeping sickness and hirsutism, as well as its potential as a chemopreventive and chemotherapeutic agent against colorectal cancer and neuroblastoma.

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Time-serial Assessment of Drug Combination Interventions in a Mouse Model of Colorectal Carcinogenesis Using Optical Coherence Tomography

Cited by 4 publications

References 64 publications

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

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

Does Mutated K-RAS Oncogene Attenuate the Effect of Sulindac in Colon Cancer Chemoprevention?

Alpha-Difluoromethylornithine, an Irreversible Inhibitor of Polyamine Biosynthesis, as a Therapeutic Strategy against Hyperproliferative and Infectious Diseases

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