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Time-serial Assessment of Drug Combination Interventions in a Mouse Model of Colorectal Carcinogenesis Using Optical
Susan LeGendre-McGhee1, Photini S Rice1, R Andrew Wall2
1Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
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.
Insights
Optical coherence tomography (OCT) accurately monitors colorectal cancer in mice. This imaging technique assessed the effectiveness of α-difluoromethylornithine (DFMO) and sulindac in preventing and treating colon tumors.
Area of Science:
- Biomedical imaging
- Oncology
- Pharmacology
Background:
- Colorectal cancer (CRC) development involves adenoma formation.
- Early detection and monitoring of CRC are crucial for effective treatment.
- Novel imaging modalities are needed for real-time assessment of CRC progression and therapeutic response.
Purpose of the Study:
- To evaluate the effectiveness of Optical Coherence Tomography (OCT) in monitoring colorectal cancer in a mouse model.
- To assess the impact of chemoprevention (CP) and chemotherapy (CT) interventions using α-difluoromethylornithine (DFMO) and sulindac on tumor development.
- To correlate OCT findings with histological and biochemical endpoints.
Main Methods:
- Utilized OCT for time-serial, nondestructive imaging of adenoma development in a mouse model of CRC.
- Administered DFMO and sulindac during early (CP) and late (CT) stages of tumorigenesis.
- Quantified biological endpoints (tumor number, tumor burden) via OCT and biochemical endpoints (Ki-67, cleaved caspase-3, COX-2, β-catenin) via immunohistochemistry.
- Analyzed K-Ras mutations using polymerase chain reaction.
Main Results:
- OCT imaging showed significant correlation with histological analysis of tumor number and burden (P < 0.0001).
- OCT enabled more accurate characterization of tumor growth rates due to its time-serial nature.
- DFMO, alone or with sulindac, suppressed tumor growth rate in the CP setting by decreasing proliferation and K-RAS mutations.
- In the CT setting, sulindac and DFMO/sulindac reduced tumor number, with decreased COX-2 staining observed.
Conclusions:
- OCT is a robust, minimally invasive method for monitoring colorectal cancer progression in mouse models.
- OCT facilitates quantitative, repeated evaluation of tumor number and burden, enabling precise measurement of therapeutic effects.
- The study demonstrates the utility of OCT in assessing the efficacy of chemopreventive and chemotherapeutic agents in CRC mouse models.
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