Inhibitory Effect Of Metformin On Rectal Aberrant Crypt Foci

Background:Colorectal cancer is one of the most common malignant cancers, and its mortality rate has risen to second place. Aberrant crypt foci(ACF) is regarded as the earliest precursor lesion of colorectal cancer. Recently, there are more and more studies about preventive drugs of ACF. One in particular is the chemopreventive effect of Nonsteroidal Antiinflammatory Drugs. There are also several reports have highlighted that the use of metformin in diabetic patients correlated with a reduced lifetime incidence of cancer. However, there are a few studies about the preventive effect of metformin against ACF and most of them are retrospective. So our team devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against ACF and its possible mechanism.Objective: To investigate inhibitory effects of metformin on rectal aberrant crypt foci and its possible mechanism.Methods: We prospectively randomized 90 nondiabetic patients with ACF to treatment with metformin(500mg bid, n=30), celecoxib(200mg bid, n=30) and no treatment(control, n=30). Each patient's age, sex, BMI, as well as drug side effects,were recorded. The lower rectal region from the middle Houston valve to the dentate line was sprayed with 0.4% methylene blue, the number of rectal ACF and its formation were counted by a magnifying colonoscopy in each patient at a baseline and after 2months' treatment. Our team also analyzed the relationship between number of rectal ACF and age. Normal rectal epithelium samples were obtained from the same trial patients by biopsy before and after treatment. Proliferation of normal rectal epithelium was detected by proliferating cell nuclear antigen(PCNA) labeling index and apoptosis was detected by terminal deoxynucleotidyl d UTP nick-end labeling(TUNEL).Moreover, to assess the state of insulin resistance, the fasting plasma glucose and serum insulin were detected.Results: One patient refused follow-up colonoscopy in control group, one stoppedtreatment early without adverse event and did not have a follow-up colonoscopy in metformin group, two patients had adverse events in celecoxib group and did not have a follow-up colonoscopy, leaving 86 patients who were included our end point analyses.We found that the number of ACF increased with age((27) 50 yrs 4.98±1.42,50-59yrs7.85±1.00,?60yrs 10.87±0.64). The mean number of ACF and other baseline clinical characteristics in three groups were similar at baseline(P(29)0.05). After 2 months, the mean number of ACF was significantly suppressed in the metformin group and celecoxib group(metformin group 7.30±2.51 before treatment vs 4.77±1.57 after 2months, P(27) 0.05; celecoxib group 7.60±2.34 before treatment vs 5.83±1.46 after 2months, P(27) 0.05), whereas, no such difference was observed in the control group(7.40±2.11 before treatment vs 7.43±2.13 after 2 months,P(29) 0.05). In the metformin group, the mean number of ACF was significantly lower, respectively, in comparison with celecoxib group(P(27)0.05). The proliferating cell nuclear antigen index of normal rectal epithelium was significantly decreased in metformin and celecoxib groups, but not in control group(control group 49.17±2.35 before treatment vs 49.23±2.42 after 2 months, P(29)0.05;metformin group 48.87±1.78 before treatment vs 27.20±1.71 after 2 months, P(27)0.05;celecoxib group 49.93±2.59 before treatment vs 36.97±1.43 after 2 months, P(27)0.05).Furthermore, the proliferating cell nuclear antigen index in metformin group was even markedly lower compared with that in celecoxib group.However, the apoptosis index(AI) remained unaltered in all groups before and after treatment(control group 3.03 ± 1.19 before treatment vs 3.00 ± 1.14 after 2 months P(29)0.05;metformin group 2.96±0.81 before treatment vs 2.93±0.78 after 2 months,P(29)0.05;celecoxib group 3.03±1.10 before treatment vs 3.07±1.08 after 2 months,P(29)0.05). The insulin resistance index also did not change significantly in all groups.Conclusions: Metformin and celecoxib can suppress rectal ACF in nondiabetic patients, moreover, the chemoprevention of metformin is more effective than celecoxib.Its mechanism may be related to the inhibition of cell proliferation, suggesting that metformin exerts an insulin-independent direct mechanism of action.