title: Suppressive effect of RAS inhibitor manumycin A on aberrant crypt foci formation in the azoxymethane-induced rat colorectal carcinogenesis model.
abstract: OBJECTIVE
  The chemopreventive effect of RAS inhibitors on colorectal cancer is unknown. Because aberrant crypt foci (ACF), earliest preneoplastic lesions, are highly positive for K-RAS mutation, RAS inhibitors are likely to be effective for chemoprevention. Therefore, in the present study, the suppressive effect of a RAS inhibitor, manumycin A, on ACF formation in an azoxymethane (AOM)-induced rat colorectal carcinogenesis model was investigated.
  
  
  METHODS
  Rats injected with AOM were administered manumycin A (30 mg/kg) subcutaneously thrice weekly for 8 weeks or for 4 weeks (latter half), sacrificed at 8 weeks, and examined for ACF in the colorectum. Phosphorylated ERK and Ki-67 expression was evaluated by immunohistochemistry. Apoptosis was assessed by TUNEL staining.
  
  
  RESULTS
  The mean number of ACF in the 8-week manumycin A group (72.9 ± 20.1) was significantly lower than in the vehicle group (155.6 ± 56.7, P < 0.01), and it was significantly lower even in the 4-week manumycin A group than in the vehicle group (92.2 ± 13.0 vs 222.3 ± 83.3, P < 0.01). The positive rate for phosphorylated ERK in the manumycin A group (13.5 ± 19.2%) was significantly lower than in the vehicle group (50.2 ± 19.8%, P < 0.01). The positive rate for Ki-67 in the manumycin A group (2.2 ± 3.4%) was significantly lower than in the vehicle group (14.7 ± 8.2%, P < 0.01). There were significantly more terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in tissue samples from the manumycin A group versus the vehicle group (8.6 ± 9.7% vs 2.9 ± 2.0%, P < 0.05).
  
  
  CONCLUSIONS
  Manumycin A suppressed ACF formation in the AOM-induced colorectal carcinogenesis model, demonstrating that RAS inhibitors may be very effective for chemoprevention of colorectal cancers.
authors.affiliation: Department of Gastroenterology and Oncology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Tsuda
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Muguruma
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Sannomiya
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Kitamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Goji
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kimura
authors.forename: Toshiya
authors.initials: T
authors.lastname: Okahisa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Takayama
mesh_terms: D058739:Aberrant Crypt Foci / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D011905:Genes, ras / Q000235:genetics; D007279:Injections, Subcutaneous; D019394:Ki-67 Antigen / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011090:Polyenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D051231:Farnesyltranstransferase; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D001397:Azoxymethane; C054474:manumycin
keywords: RAS inhibitor; aberrant crypt foci; colorectal cancer; manumycin A cancer prevention