title: Effect of zinc supplementation on N-nitrosomethylbenzylamine-induced forestomach tumor development and progression in tumor suppressor-deficient mouse strains.
abstract: Zinc deficiency is associated with high incidences of esophageal and other cancers in humans and leads to a highly proliferative hyperplastic condition in the upper gastrointestinal tract in laboratory rodents. Zn replenishment reduces the incidence of lingual, esophageal and forestomach tumors in Zn-deficient rats and mice. While previous animal studies focused on Zn deficiency, we have investigated the effect of Zn supplementation on carcinogenesis in Zn-sufficient mice of wild-type and tumor suppressor-deficient mouse strains. All mice received N-nitrosomethylbenzylamine and half the mice of each strain then received Zn supplementation. At killing, mice without Zn supplementation had developed more tumors than Zn-supplemented mice: wild-type C57BL/6 mice developed an average of 7.0 versus 5.0 tumors for Zn supplemented (P < 0.05); Zn-supplemented Fhit-/- mice averaged 5.7 versus 8.0 for control mice (P < 0.01); Zn-supplemented Fhit-/-Nit1-/- mice averaged 5.4 versus 9.2 for control mice (P < 0.01) and Zn-supplemented Fhit-/-Rassf1a-/- (the murine gene) mice averaged 5.9 versus 9.1 for control mice (P < 0.01). Zn supplementation reduced tumor burdens by 28% (wild-type) to 42% (Fhit-/-Nit1-/-). Histological analysis of forestomach tissues also showed significant decreases in severity of preneoplastic and neoplastic lesions in Zn-supplemented cohorts of each mouse strain. Thus, Zn supplementation significantly reduced tumor burdens in mice with multiple tumor suppressor deficiencies. When Zn supplementation was begun at 7 weeks after the final carcinogen dose, the reduction in tumor burden was the same as observed when supplementation began immediately after carcinogen dosing, suggesting that Zn supplementation may affect tumor progression rather than tumor initiation.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.forename: James
authors.initials: J
authors.lastname: Liu
authors.forename: Xueliang
authors.initials: X
authors.lastname: Pan
authors.forename: Donald
authors.initials: D
authors.lastname: Quimby
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.forename: Teresa
authors.initials: T
authors.lastname: Druck
authors.forename: Gerd P
authors.initials: GP
authors.lastname: Pfeifer
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Louise Y
authors.initials: LY
authors.lastname: Fong
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000502:physiology*; D000619:Aminohydrolases / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D019587:Dietary Supplements; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives / Q000633:toxicity; D018450:Disease Progression; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000502:physiology*; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D017967:Zinc Compounds / Q000008:administration & dosage*; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D000619:Aminohydrolases; D002273:Carcinogens; D004128:Dimethylnitrosamine; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D017967:Zinc Compounds; D000099170:Bis(5'-adenosyl)triphosphatase; C014707:nitrosobenzylmethylamine; C021867:nitrilase