Carcinogenesis, Vol 18, 1477-1484, Copyright © 1997 by Oxford University Press
LY Fong, KM Lau, K Huebner and PN Magee
Dietary zinc deficiency in rats induces hyperplasia in the esophagus and
increases N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumor
incidence. Previous work showed a direct relationship between epithelial
cell proliferation and esophageal tumor incidence in rats given multiple
doses of NMBA. We investigated the effects of single low doses of NMBA in
zinc-deficient rats since a single dose of 5.0 mg/kg was reported to be
non-carcinogenic in rats. Zinc-sufficient and deficient rats received a
single i.g. dose of NMBA at 0.5 or 2.0 mg/kg. At week 14, tumor incidence
was 50% with 0.8 +/- 1.0 tumors/rat, and 80% with 2.2 +/- 1.9 tumors/rat,
in deficient groups, D(0.5) and D(2.0), that received the lower and higher
dose, respectively. In addition, two small papillomas were found in one out
of eight untreated zinc-deficient rats. None of the NMBA-treated or
untreated zinc- sufficient rats had any tumors. Esophageal cell
proliferation, as determined by proliferating cell nuclear antigen (PCNA)
immunohistochemistry, showed that, irrespective of NMBA treatment,
deficient esophagi had significant increases in the number of labeled
cells, the total number of cells, and the labeling index, as compared with
zinc-sufficient ones. Mutations in Ha-ras and p53 genes in esophageal
tumors were detected by single strand conformation polymorphism (SSCP)
analysis. DNA sequencing of variant conformers revealed a point mutation
(GGA-->GAA, codon 12) in Ha-ras in 4/5 (80%) and 5/8 (63%) tumors, from
D(0.5) and D(2.0) rats, respectively. Three out of eight tumors from D(2.0)
rats exhibited SSCP mobility shifts within p53 exons 5 and 7: two tumors
(2/8, 25%) had missense mutations and the third, a silent mutation. Of the
two tumors with p53 mutations, one had a double mutation (transition at
codon 164, TCA-->TTA; transversion at codon 241, AGT-->TGT), and the
other tumor, a transition at codon 172 (AGA-->GGA), with amino acid
changes in all cases. In parallel with PCNA expression, elevated p53
expression was associated with hyperplastic and dysplastic regions, as well
as with tumors, in deficient esophagi. In short, these data indicate that
dietary zinc deficiency, with its associated sustained increased cell
proliferation in the esophagus, can drive an otherwise non-tumorigenic dose
of NMBA into a highly tumorigenic one.
ARTICLES
Induction of esophageal tumors in zinc-deficient rats by single low doses of N-nitrosomethylbenzylamine (NMBA): analysis of cell proliferation, and mutations in H-ras and p53 genes
Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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