Abstract A25: Inhibition or delay of microadenoma development by atorvastatin, naproxen and ED-71 in mice genetically predisposed to colorectal adenomas
Authors: Chang Wen-Chi L. , Cooper Harry S. , Hensley Harvey , Li Tianyu , Devarajan Karthik , Clapper Margie L. 
Published: March 2017

Abstract
Previous studies by this group demonstrate the ability of chemopreventive agents to differentially inhibit morphological subtypes (flat and polypoid) of colorectal adenomas. Recent efforts have focused on the response of microadenomas, a lesion not routinely evaluated by others, to therapeutic intervention. Microadenomas, or dysplastic aberrant crypt foci (ACFs), are direct precursors of colorectal adenomas and represent the earliest microscopic aberration that can be detected prior to colon tumor formation. The goal of the present study was to: 1) characterize the incidence and multiplicity of microadenomas (≤4 crypts) in Apc+/Min-FCCC mice that spontaneously develop multiple colorectal adenomas, and 2) compare the effect of three classes of chemopreventive agents on microadenoma formation. Animals for baseline histological characterization were subjected to colonoscopic examinations at 7 weeks of age (standard time of treatment initiation) and categorized as tumor-free or tumor-bearing. Forty five percent of the Apc+/Min-FCCC mice without gross colon tumors (N=11) possessed microadenomas at baseline, with an overall average of 0.63 ± 0.29 (Mean ± SEM) per mouse. Among mice with gross tumors at baseline (N=10), 30% had microadenomas (0.3 ± 0.16). Results from treatment studies demonstrate that several agents have the ability to modulate microadenoma formation or progression when administered chronically for 14 weeks. First, atorvastatin (100 ppm), a cholesterol-lowering agent, completely eliminated the formation of microadenomas in mice that were free of gross tumors at baseline (as compared to controls, P = 0.007). In addition, a 33% reduction in tumor incidence was observed among atorvastatin-treated animals at 14 weeks as compared to controls (atorvastatin vs. controls: 55.6% vs. 88.5%, P = 0.017). Second, administration of the non-steroidal anti-inflammatory drug naproxen (400 ppm) caused a significant reduction (89.3%) in the multiplicity of microadenomas as compared to that of animals receiving unsupplemented control diet (0.06 ± 0.06 vs. 0.56 ± 0.24, respectively). Inhibition of microadenomas by naproxen translated into a significant reduction in tumor incidence, (naproxen - 64.7%, controls - 100%, P = 0.0076). Third, ED-71 (eldecalcitol; 1α,25-dihydroxy-2β;-(3-hydroxypropyloxy) Vitamin D3), a novel analog of calcitriol, at a dose of 0.1 μg/kg bw, unexpectedly increased the multiplicity of microadenomas in drug-treated mice as compared to controls (0.9 ± 0.22 vs. 0.5 ± 0.25 P = 0.06, respectively). In contrast, ED-71 reduced the mean incidence of adenomas (&gt; 4 crypts) by 47% (ED-71 - 45.5%, controls 92.3%; P = 0.02) and adenoma multiplicity by 47.6% (ED-71 - 1.1 ± 0.39, controls - 2.1 ± 0.72; P &gt; 0.05) in mice that were free of gross tumors at baseline. These data suggest that ED-71 is effective in preventing the progression of microadenomas to adenomas. In summary, these findings demonstrate the importance of evaluating the response of microadenomas to therapy and suggest that microadenomas represent a promising target for chemopreventive intervention.
Supported by CA129467, N01CN43309 and HHSN2610005. * Equal contribution to the abstract.
Citation Format: Wen-Chi L. Chang, Harry S. Cooper, Harvey Hensley, Tianyu Li, Karthik Devarajan, Margie L. Clapper. Inhibition or delay of microadenoma development by atorvastatin, naproxen and ED-71 in mice genetically predisposed to colorectal adenomas. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A25.