Toxicological Sciences, Vol 52, 17-23, Copyright © 1999 by Society of Toxicology
H Hikita, J Vaughan, K Babcock and HC Pitot
Studies of the multistage nature of hepatocarcinogenesis in the rat have
led to the development of models having significant potential application
to carcinogenesis in other tissues as well as other species. Whereas the
initial and final stages of carcinogenesis- initiation and
progression-involve genetic changes and are operationally irreversible, the
intermediate stage of promotion is operationally reversible and can be
modulated by a variety of environmental factors. Numerous investigations
have demonstrated that chronic caloric restriction modifies neoplastic
development, primarily during the stage of promotion, so that fewer lesions
develop. Short- term fasting of rats, initiated with a nonnecrogenic dose
of diethylnitrosamine (DEN) and promoted with 0.05% phenobarbital (PB) for
4 weeks, results in loss of virtually all of the measurable altered hepatic
foci (AHF) after two 5-day periods of fasting with an intermediate 2-day
period of feeding. This change was accompanied by a marked decrease in
bromodeoxyuridine (BrdU) labeling of hepatocytes within AHF together with a
significant increase in apoptosis of such cells measured by nick
end-labeling. Similar but lesser effects were noted in surrounding,
nonfocal hepatocytes. On refeeding, both the numbers and volume percentage
of AHF returned within 2 weeks to values seen in nonfasted controls.
Administration of PB during the fasting period did not alter these results,
although AHF reappeared more rapidly in such animals on refeeding. Nuclear
DNA fragmentation was evident in samples of whole liver from fasted
animals. During this same period the expression of c-myc mRNA increased 3-
to 9-fold, while levels of albumin and insulin-like growth factor I mRNAs
decreased significantly. This study demonstrates a model system in which
the reversibility of the effects of promoting agents may be rapidly
determined and the effects of chemopreventive inhibitors of promotion may
be rapidly evaluated.
ARTICLES
Short-term fasting and the reversal of the stage of promotion in rat hepatocarcinogenesis: role of cell replication, apoptosis, and gene expression
McArdle Laboratory for Cancer Research and The Center for Environmental Toxicology, University of Wisconsin-Madison, 53706-1599, USA.
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