Læknablaðið - 15.10.1983, Blaðsíða 33

LÆKNABLADID
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the more efficient repair of the lesion, may
account for its lack of carcinogenicity.
Based on the available data, no general
correlation between chemically induced DNA
damage and species differences in tumor
induction can be made. That such a correlation
may exist, however, is not inconsistent with
the data presently available.
C. Proliferative Status of Target Cells
There may be a fundamental difference in the
consequences of error accumulation between
DNA of dividing and nondividing cells. In
dividing cells, one is mainly concerned with
replicative error propagation; that is, the
transmission of mistakes in DNA replication
from one generation to the next. Mechanisms
which enhance the frequency of such mistakes
could involve alterations in the DNA synthetic
apparatus and have been referred to as
intrinsic mutagenesis (4). In nondividing cells,
one is mainly concerned with the accumula-
tion of unrepaired DNA damage. In the
mechanism of carcinogenesis, consideration is
normally limited to either dividing cells or to
resting cells destined to undergo at least one
further division cycle. If damaged DNA is
repaired by a faithful, »error-free« mecha-
nism, the damage is probably inconsequfential
with respect to cancer. Misrepair of DNA
damage as a mechanism of cancer is possible
since there is substantial evidence for the
induction of an error-prone repair pathway
(SOS) in bacteria and eukaryotes (15, 78). The
underlying concept of this repair pathway is
that it can alleviate potentially lethal damage,
but only with a high probability of inducing
mutations. The induction of this pathway
could be a programmed expression of cancer
or could be permanently induced by damage
to DNA at a site that regulates this pathway.
The importance of DNA replication in the
development of tumors has been extensively
studied. Replication is required for fixation of
DNA damage and the progression of a
dormant initiated cell to a clinically recog-
nized tumor (20). Thus, the next stage in
carcinogenesis (promotion) involved a loss of
response to normal control of cell prolifera-
tion (29, 30), and only a few rounds of DNA
replication may be needed to amplify and
stabilize errors introduced by chemical carci-
nogens. Several compounds such as perchlo-
roethylene, chloroform, or 1,4-dioxane, which
are minimally genotoxic in most bacterial
tests, induce tumors in mice while causing
substantial necrosis in the target tissues. The
mechanism underlying the tumor formation by
these compounds is unclear. However, a
hypothesis has been proposed postulating the
restorative hyperplasia from the cytotoxicity
of these compounds as the mechanism for
tumor formation (69). This might occur by
either growth stimulation of pre-existing
transformed cells to the extent that they
become independent of normal physiological
growth inhibitors, or by increasing the chan-
ces for errors during the DNA replication
process. Manipulating the rate of cellular
proliferation may thus modify the tumor
incidence as has been shown with partial
hepatectomy, methylnitrosourea, dimethylni-
trosourea, benzo(a)pyrene, diet, drugs, natural
physiological agents (hormones, bile acids) or
the stimulated regenerative hyperplasia result-
ing from the toxic effect of carbon tetrachlo-
ride and 2-acetylaminofluorene (69). On the
other hand, the stabilization of the differentiat-
ed nondividing state of epithelial cells by
retinoids has been used as a way of inhibiting
mammary and colon carcinogenesis (42, 47).
The degree of normal replication potential
and the relative effect of various exogenous
and endogenous agents on the rate of this
process may, to a large extent, determine the
susceptibility to chemical carcinogens.
III. PROMOTION
A. Effects of Promoters
Tumor promotion is experimentally defined as
the appearance of tumors induced by sequen-
tial treatment of animals with an initiator
(such as an incomplete carcinogen or a low
dose of a complete carcinogen) followed by
long-term application of a promoter. Under
the same experimental conditions, neither
initiator nor promoter alone can induce tu-
mors, nor can a regimen of promoter first
followed by initiator. Thus, the requirement
for synergistic effects between initiators and
promoters in order to induce tumor formation
is a critical feature of the initiation-promotion
systems.
A long interval between application of
initiator and promoter will still produce tu-
mors since initiators induce a stable or perma-