Acyclic retinoid inhibits colon carcinogenesis

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3056 Background and objective: Acyclic retinoid (ACR) has recently been demonstrated by us to inhibit the in vitro growth of human carcinoma cells by modulating the expression levels of the cell cycle-related molecules. We then investigated cancer preventive effect of ACR in the colon carcinogenesis animal models. Materials and methods: Exp. 1: Eight-week-old male and female Min mice in groups 2 and 3 were fed a diet containing 50 and 150 ppm ACR, respectively, for 13 weeks. Mice in group 1 were given the control diet alone. Exp. 2: Five-week-old male F344 rats were randomly assigned to the experimental groups. Rats in groups 1-3 received subcutaneous injections of 1,2-dimethylhydrazine (DMH) once a week for 2 weeks to induce aberrant crypt foci (ACF). One week before the first injection of DMH, rats in groups 2 and 3 were fed a diet containing 50 and 150 ppm ACR, respectively, for 5 weeks. Rats in group 4 were fed a diet containing 150 ppm ACR. Rats in group 5 were given the control diet alone and served as untreated controls. The rats were sacrificed at 5 weeks after the start of the experiment. Exp. 3: Five-week-old male F344 rats in groups 1-3 were given subcutaneous injections of DMH once a week for 2 weeks. Starting 1 week after the last injection, the rats received 1% dextran sodium sulfate (DSS) in drinking water for 1 week. One week after the DSS treatment, rats in groups 2 and 3 were fed a diet containing 50 and 150 ppm ACR, respectively, for 16 weeks. Rats in group 4 were fed a diet containing 150 ppm ACR. Rats in group 5 were given the control diet alone and served as untreated controls. The rats were sacrificed at 16 weeks after the start of the experiment. Results: (Exp. 1) ACR caused a significant decrease in tumor multiplicity and size compared to the control group ( P <0.05). (Exp. 2) Oral administration at both dose levels of ACR significantly decreased the number of ACF compared to the control group. ACR also inhibited proliferating nuclear cell antigen (PCNA) positive index and the levels of expression of the cyclin D1 protein and increased apoptotic index in the colonic epithelial cells treated with DMH. (Exp. 3) Continuous oral administration at both dose levels of ACR caused a significant decrease in tumor multiplicity ( P <0.005) and volume ( P <0.05) compared to the control group. ACR also decreased the PCNA positive index and induced apoptosis in the colon tumor. Treatment of the animals with ACR did not cause any toxic side effects in any of the organ examined. In parallel studies, we also found that the combination of ACR and TX-402, an antiangiogenic hypotoxic cytotoxin, exerted synergistic inhibition of the growth of HT29 human colon carcinoma cells. Conclusions: These results suggest that ACR suppresses colon carcinogenesis by inhibiting cell proliferation and by inducing apoptosis. Therefore, ACR may be a valuable compound in the chemoprevention and therapy of human colon cancer.