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.
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.
Martin
Keith R
KR
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
Saulnier
Muriel J
MJ
Kari
Frank W
FW
Barrett
J Carl
JC
French
John E
JE
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
D000975:Antioxidants; D016166:Free Radical Scavengers; D000111:Acetylcysteine