Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial.
The biguanide metformin is widely used for treating diabetes mellitus. We previously showed the chemopreventive effect of metformin in two rodent models of colorectal carcinogenesis. However, besides epidemiologic studies, little is known about the effects of metformin on human colorectal carcinogenesis. The objective of this pilot study was to evaluate the chemopreventive effect of metformin on rectal aberrant crypt foci (ACF), which are an endoscopic surrogate marker of colorectal cancer. We prospectively randomized 26 nondiabetic patients with ACF to treatment with metformin (250 mg/d, n = 12) or no treatment (control, n = 14); 23 patients were evaluable for end point analyses (9 metformin and 14 control); the two groups were similar in ACF number and other baseline clinical characteristics. Magnifying colonoscopy determined the number of rectal ACF in each patient at baseline and after 1 month in a blinded fashion (as were all laboratory end point analyses). We also examined proliferative activity in colonic epithelium (via proliferating cell nuclear antigen labeling index) and apoptotic activity (via terminal deoxynucleotidyl transferase dUTP nick-end labeling). At 1 month, the metformin group had a significant decrease in the mean number of ACF per patient (8.78 +/- 6.45 before treatment versus 5.11 +/- 4.99 at 1 month, P = 0.007), whereas the mean ACF number did not change significantly in the control group (7.23 +/- 6.65 versus 7.56 +/- 6.75, P = 0.609). The proliferating cell nuclear antigen index was significantly decreased and the apoptotic cell index remained unaltered in normal rectal epithelium in metformin patients. This first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer.
Hosono
Kunihiro
K
Division of Gastroenterology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Endo
Hiroki
H
Takahashi
Hirokazu
H
Sugiyama
Michiko
M
Sakai
Eiji
E
Uchiyama
Takashi
T
Suzuki
Kaori
K
Iida
Hiroshi
H
Sakamoto
Yasunari
Y
Yoneda
Kyoko
K
Koide
Tomoko
T
Tokoro
Chikako
C
Abe
Yasunobu
Y
Inamori
Masahiko
M
Nakagama
Hitoshi
H
Nakajima
Atsushi
A
D058739:Aberrant Crypt Foci / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D000236:Adenoma / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic / Q000379:methods; D015179:Colorectal Neoplasms / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology; D008055:Lipids / Q000097:blood; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D010865:Pilot Projects; D012007:Rectum / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D008055:Lipids; D008687:Metformin