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BMC Cancer. 2012; 12: 118.
Published online Mar 26, 2012. doi:  10.1186/1471-2407-12-118
PMCID: PMC3353167
Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial
Takuma Higurashi,1 Hirokazu Takahashi,1 Hiroki Endo,1 Kunihiro Hosono,1 Eiji Yamada,1 Hidenori Ohkubo,1 Eiji Sakai,1 Takashi Uchiyama,2 Yasuo Hata,2 Nobutaka Fujisawa,3 Shiori Uchiyama,4 Akiko Ezuka,4 Hajime Nagase,4 Takaomi Kessoku,5 Nobuyuki Matsuhashi,6 Shoji Yamanaka,7 Yoshiaki Inayama,7 Satoshi Morita,8 and Atsushi Nakajimacorresponding author1,9
1Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan
2Department of Gastroenterology, Chigasaki Municipal Hospital, Kanagawa, Japan
3Gastroenterology Division, Tokyo Metropolitan Hiroo Hospita, Tokyo, Japan
4Department of Gastroenterology, Yokohama Rosai Hospital, Yokohama, Japan
5Department of Gastroenterology, Hiratsuka City Hospital, Kanagawa, Japan
6Department of Gastroenterology, Kanto Medical Center, NTT East, Tokyo, Japan
7Department of Pathology, Yokohama City University, Yokohama, Japan
8Department of Biostatistics and Epidemiology, Yokohama City University School of Medicine, Yokohama, Japan
9Division of Gastroenterology, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan
corresponding authorCorresponding author.
Takuma Higurashi: takumahigurashi/at/yahoo.co.jp; Hirokazu Takahashi: hirokazu/at/med.yokohama-cu.ac.jp; Hiroki Endo: endo1978/at/yokohama-cu.ac.jp; Kunihiro Hosono: hiro1017/at/fukuhp.yokohama-cu.ac.jp; Eiji Yamada: eiji/at/yokohama-cu.ac.jp; Hidenori Ohkubo: ohkuboh/at/yokohama-cu.ac.jp; Eiji Sakai: eiji-not_found/at/mail.goo.ne.jp; Takashi Uchiyama: maruru0203/at/yahoo.co.jp; Yasuo Hata: yhata-gi/at/umin.ac.jp; Nobutaka Fujisawa: fujisawa-yokohama2640/at/hotmail.co.jp; Shiori Uchiyama: shiori_u_0120/at/yahoo.co.jp; Akiko Ezuka: aki_ezuka/at/yahoo.co.jp; Hajime Nagase: nagase/at/yokohamah.rofuku.go.jp; Takaomi Kessoku: takaomi-kesso/at/hotmail.co.jp; Nobuyuki Matsuhashi: nmatuha-tky/at/umin.ac.jp; Shoji Yamanaka: shojiy/at/yokohama-cu.ac.jp; Yoshiaki Inayama: inayama/at/yokohama-cu.ac.jp; Satoshi Morita: smorita/at/urahp.yokohama-cu.ac.jp; Atsushi Nakajima: nakajima-tky/at/umin.ac.jp
Received December 27, 2011; Accepted March 26, 2012.
Abstract
Background
Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients.
Methods/Design
This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation.
Discussion
This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been reported to be at a lower risk of cancer development than those not taking under treatment with metformin. We showed in a previous study that metformin suppressed the formation of human colorectal ACF. We therefore decided to conduct a study to determine whether metformin might suppress the formation of human colorectal polyps.
Trial registration
This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000006254
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