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

• Type of Material: Article
• Authors: Susan LeGendre-McGhee, University of Arizona; Photini S. Rice, University of Arizona; R. Andrew Wall, University of Arizona; Kyle J. Sprute, University of Arizona; Ramireddy Bommireddy, Emory University; Amber M. Luttman, University of Arizona; Raymond B. Nagle, University of Arizona; Edward R. Abril, University of Arizona; Katrina Farrell, University of Arizona; Chiu-Hsieh Hsu, University of Arizona; Denise J. Roe, University of Arizona; Eugene W. Gerner, University of Arizona; Natalia A. Ignatenko, University of Arizona; Jennifer K. Barton, University of Arizona
• Language: English
• Date: 2015-09-07
• Publisher: Libertas Academica
• Publication Version: Final Published Version
• Copyright Statement: © 2015 the author(s), publisher and licensee Libertas Academica Ltd.
• License: Creative Commons Attribution-Noncommercial 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.4137/CGM.S21216
• Title of Journal or Parent Work: Cancer Growth and Metastasis
• ISSN: 1179-0644
• Volume: 8
• Issue: Suppl 1
• Start Page: 63
• End Page: 80
• Grant/Funding Information: University of Arizona Cancer Center Support Grant (including usage of Shared Resources) P30CA023074.; Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers R01CA109835, R01CA157595, and P50CA095060.
• Keywords: optical coherence tomography; α-difluoromethylornithine; sulindac; mouse model; colorectal cancer
• Research Categories: Chemistry, Biochemistry; Physics, Optics; Engineering, Biomedical

Abstract

Optical coherence tomography (OCT) is a high-resolution, nondestructive imaging modality that enables time-serial assessment of adenoma development in the mouse model of colorectal cancer. In this study, OCT was utilized to evaluate the effectiveness of interventions with the experimental antitumor agent α-difluoromethylornithine (DFMO) and a nonsteroidal anti-inflammatory drug sulindac during early [chemoprevention (CP)] and late stages [chemotherapy (CT)] of colon tumorigenesis. Biological endpoints for drug interventions included OCT-generated tumor number and tumor burden. Immunochistochemistry was used to evaluate biochemical endpoints [Ki-67, cleaved caspase-3, cyclooxygenase (COX)-2, β-catenin]. K-Ras codon 12 mutations were studied with polymerase chain reaction-based technique. We demonstrated that OCT imaging significantly correlated with histological analysis of both tumor number and tumor burden for all experimental groups (P < 0.0001), but allows more accurate and full characterization of tumor number and burden growth rate because of its time-serial, nondestructive nature. DFMO alone or in combination with sulindac suppressed both the tumor number and tumor burden growth rate in the CP setting because of DFMO-mediated decrease in cell proliferation (Ki-67, P < 0.001) and K-RAS mutations frequency (P = 0.04). In the CT setting, sulindac alone and DFMO/sulindac combination were effective in reducing tumor number, but not tumor burden growth rate. A decrease in COX-2 staining in DFMO/sulindac CT groups (COX-2, P < 0.01) confirmed the treatment effect. Use of nondestructive OCT enabled repeated, quantitative evaluation of tumor number and burden, allowing changes in these parameters to be measured during CP and as a result of CT. In conclusion, OCT is a robust minimally invasive method for monitoring colorectal cancer disease and effectiveness of therapies in mouse models.