title: Timing of supplementation with the antioxidant N-acetyl-L-cysteine reduces tumor multiplicity in novel, cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) transgenic mice but has no impact on malignant progression.
abstract: Epidemiological studies support the protective role of dietary antioxidants in preventing cancer. However, emerging evidence suggests that antioxidant supplements may actually exacerbate carcinogenesis. We explored this paradox in a model containing two common genotypic characteristics of human cancers. We selected p53 haploinsufficient Tg.AC (v-Ha-ras) mice as a model, because it contains an activated, carcinogen-inducible ras oncogene and an inactivated p53 tumor suppressor gene. These mice develop chemically induced benign and malignant skin tumors rapidly. Mice were fed basal diet with or without 3% N-acetyl-L-cysteine (NAC) before and after topical application of the carcinogen benzo[a]pyrene (64 micrograms twice per week for 7 wk) until 50% of mice within a group displayed at least one lesion. Half each of mice fed the basal and the NAC-supplemented diet were then switched to the alternate diet. Mice fed the NAC-supplemented diet or switched from the NAC-supplemented to the basal diet displayed 38% and 26% reductions, respectively, in tumor multiplicity and a 15% reduction if switched from the basal to the NAC-supplemented diet. Although latency was unaffected, NAC induced a lag in tumor incidence, which exceeded 90% at 10 wk for all groups. The timing of NAC supplementation did not affect malignant progression. Thus dietary NAC was chemoprotective by slowing tumorigenesis but did not affect malignant conversion.
authors.affiliation: Transgenic Carcinogenesis Unit, Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. krm12@psu.edu
authors.forename: Keith R
authors.initials: KR
authors.lastname: Martin
authors.forename: Muriel J
authors.initials: MJ
authors.lastname: Saulnier
authors.forename: Frank W
authors.initials: FW
authors.lastname: Kari
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
authors.forename: John E
authors.initials: JE
authors.lastname: French
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D018592:Cross-Over Studies; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage*; D011905:Genes, ras / Q000235:genetics*; D016014:Linear Models; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012509:Sarcoma / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D015996:Survival Rate; D013997:Time Factors
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D000111:Acetylcysteine