Carcinogenesis, Vol 18, 553-559, Copyright © 1997 by Oxford University Press
WG Qing, CJ Conti, M LaBate, D Johnston, TJ Slaga and MC MacLeod
Existing models of mouse mammary carcinogenesis induced by the model
polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA)
typically use a small number of bolus doses applied intragastrically. In
contrast to this, typical human exposures to carcinogens are thought to be
at lower doses and to occur with chronic or sporadic timing. When the
classical dosage (1 mg DMBA given once a week for 6 weeks) was split into
five daily doses of 200 microg given intragastrically to female SENCAR mice
each week for 6 weeks, toxicity was high and the major tumor type seen was
lymphoma. Lowering the dose to 60 microg/day gave less toxicity, a 75%
incidence of lymphoma and a 30% incidence of mammary carcinoma. However, 20
microg DMBA given five times per week for 6 weeks resulted in a 65-70%
incidence of mammary carcinoma within approximately 50 weeks. This
represents a 50-fold lower daily dosage of DMBA than that used in the
classical model. DNA was prepared from 10 mammary adenocarcinomas and 10
lymphomas and exons 1 and 2 of the H- ras1, K-ras and N-ras genes were
sequenced using PCR techniques. Mutations altering codons 12 or 61 of one
of the ras family genes were found in 4/10 mammary carcinomas and 5/10
lymphomas. Three mammary tumors exhibited codon 61 mutations, one in each
of the genes studied, and a fourth tumor contained a codon 12 mutation in
the K-ras gene. Among the lymphomas, two mutations in codon 12 of K-ras,
one mutation in codon 61 of K-ras and two mutations in codon 61 of N-ras
were also found. Each of the mutations could be interpreted as a G-->T
or A-->T transversion. It is suggested that the high incidence of
lymphoma at the higher, repetitive doses may be related to immunotoxicity.
These low dose models of lymphomagenesis and mammary carcinogenesis should
prove useful for tests of chemopreventive agents that target the initiation
phase of carcinogenesis.
ARTICLES
Induction of mammary cancer and lymphoma by multiple, low oral doses of 7,12-dimethylbenz[a]anthracene in SENCAR mice
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville 78957, USA.
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