title: Time-serial Assessment of Drug Combination Interventions in a Mouse Model of Colorectal Carcinogenesis Using Optical Coherence Tomography.
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.
authors.affiliation: Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: LeGendre-McGhee
authors.affiliation: Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: Photini S
authors.initials: PS
authors.lastname: Rice
authors.affiliation: College of Optical Sciences, University of Arizona, Tucson, AZ, USA.
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Wall
authors.affiliation: Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Sprute
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Ramireddy
authors.initials: R
authors.lastname: Bommireddy
authors.affiliation: College of Optical Sciences, University of Arizona, Tucson, AZ, USA.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Luttman
authors.affiliation: Department of Pathology, University of Arizona, Tucson, AZ, USA.
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Nagle
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Abril
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Farrell
authors.affiliation: Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
authors.forename: Chiu-Hsieh
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA. ; Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Roe
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Eugene W
authors.initials: EW
authors.lastname: Gerner
authors.affiliation: University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA. ; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Ignatenko
authors.affiliation: Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA. ; College of Optical Sciences, University of Arizona, Tucson, AZ, USA. ; University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Barton
keywords: colorectal cancer; mouse model; optical coherence tomography; sulindac; α-difluoromethylornithine