Abstract 195: Effect of sulindac and/or atorvastatin on colorectal adenomas in the Apc+/Min-FCCC mouse model varies depending on the presence or absence of adenomas at the time of drug initiation.

Abstract

While treatment with sulindac plus atorvastatin has been shown to be more efficacious than either agent alone in inhibiting chemically-induced colorectal tumors, the effectiveness of this same drug combination against sporadic colorectal cancer has not been evaluated. The goal of this study was to assess the chemopreventive activity of sulindac plus atorvastatin, in combination, in a unique strain of Apc+/Min-FCCC mice that spontaneously develops colorectal adenomas at a high multiplicity and incidence. Male Apc+/Min-FCCC mice (6-8 weeks of age) were subjected to colonoscopic examinations at baseline (prior to treatment) and randomized to receive either control chow or chow supplemented with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac plus atorvastatin for 100 days. All drugs were well tolerated, with no significant change in body weight observed among the treatment groups. At the time of euthanasia, gross small intestinal (SI) and colonic tumors were identified and the height, width and length of the colonic tumors was measured using calipers. Only the colon was submitted for histopathological evaluation. The multiplicity of gross SI tumors was decreased in animals administered sulindac (54%) or sulindac plus atorvastatin (41%), as compared to those receiving either control diet or atorvastatin alone (P ≤ 0.00024). Based on the results of the colonoscopic evaluation, mice were categorized as being tumor-free or tumor-bearing at baseline. Treatment with atorvastatin, alone or in combination, lead to a 2.4-3.6-fold increase in the percentage of mice that were tumor-free both at baseline and at the time of euthanasia: control 12.5%; sulindac 9.1%; atorvastatin 44.4% and sulindac plus atorvastatin 30%. Interestingly, atorvastatin completely inhibited the formation of microadenomas in mice that were tumor-free at baseline (P = 0.002). In mice that were tumor-bearing at baseline, only the sulindac plus atorvastatin combination therapy reduced the multiplicity of colon adenomas significantly as compared to that of controls (Mean ± SEM, 3.7 ± 0.7 and 6.4 ± 1.2, respectively) (P = 0.049). The effect of drug exposure on tumor volume was evaluated at the time of euthanasia. Colon tumor volume was reduced 2-fold in mice treated with sulindac as compared to that of mice administered control diet or diet supplemented with atorvastatin or sulindac plus atorvastatin in combination (P < 0.03). These data suggest that the chemopreventive activity of sulindac and/or atorvastatin against colorectal adenomas is dictated in part by the status of the animal (tumor-free or tumor-bearing) at the time treatment is initiated. Additional experimentation is required to establish the patient subgroup and drug schedule that will yield optimal therapeutic activity in a clinical setting. (Supported by NIH R21CA129467) Citation Format: Wen-Chi Chang, Christina Ferrara, Stacy Mosier, Harry Cooper, Karthik Devarajan, Harvey Hensley, Tianyu Li, Margie Clapper. Effect of sulindac and/or atorvastatin on colorectal adenomas in the Apc+/Min-FCCC mouse model varies depending on the presence or absence of adenomas at the time of drug initiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 195. doi:10.1158/1538-7445.AM2013-195