Læknablaðið - 15.10.1983, Side 31

LÆKNABLAÐID
253
DNA tumor viruses, however, would most
likely proceed according to the first mecha-
nism, with the viruses providing additional
genetic information to the cellular DNA.
However, recent work with RNA tumor
viruses (retroviruses) has resulted in identifi-
cation of cellular homologs of retrovirus
transforming genes (13). Thus, expression of
normal and/or mutated cellular genes may,
under certain conditions (such as by transfecti-
on experiments in NIH 3T3 cells), initiate
oncogenic transformation (7, 52). Clearly, a
considerable amount of work is needed to sort
out the physiological role of these cellular
oncogenes in carcinogenesis.
The alteration of DNA by chemical carcino-
gens or radiation has many important implica-
tions. The first of these is that unless the
damage is repaired, a mutation may result and
because of this an increased risk of tumor
induction may exist. Many studies have focu-
sed on the factors involved in repairing DNA
and on the process of DNA synthesis (60).
Much knowledge has been acquired on bacte-
rial systems, and more recently with eukaryo-
tes. In addition, it has been found that certain
agents, such as asbestos (26) and heavy metals
(37) may increase the incidence of tumors by
altering either DNA synthesis or its repair.
Concomitant with this increased knowledge
on DNA repair, it has become possible to
determine the structural alterations caused in
DNA by chemical carcinogens and radiation
(23). This had occurred only because of recent
advances in spectroscopic instrumentation,
especially in the areas of nuclear magnetic
resonance and mass spectroscopy (48). Even
newer techniques are being developed, such as
radioimmunoassays with monoclonal antibo-
dies (55), that should allow estimation of DNA
damage in humans. Since it is possible to
measure the DNA damage caused by both
chemical carcinogens and radiation, the resul-
ting biological effects induced by this damage
can now be studied. Recent breakthroughs in
DNA sequencing techniques and recombinant
DNA technology can be combined with che-
mical, physical and enzymatic analysis of DNA
damage and repair to increase our understan-
ding of these problems.
Based on the data obtained to date, it is
possible to propose a unified working theory
which combines all of these aspects. Chemical
carcinogens must be metabolically activated
to reactive (electrophilic) species capable of
covalent interactions with informational ma-
cromolecules. Since man is a genetically heter-
ogeneous species, there may be variations in
this metabolic activation process which may
partly explain why certain individuals show
increased cancer risk. The interaction between
the activated carcinogen and DNA, as well as
DNA interactions with ionizing and UV radia-
tion, cause structural perturbations in the
macromolecule. Unless this damage is repai-
red there may be an increased risk of tumor
formation. Part of the DNA damage induced
by chemical carcinogens or radiation may
occur in control regions (promoter regions)
which normally suppress the expression of the
so-called »oncogenes« (7, 52). With the dama-
ge present, these genes may be activated and
result in the occurrence of a transformed
phenotype. Alternatively, the DNA damage
may lead to a mutation in a cellular oncogene
(transforming gene) that results in modificati-
on of the gene (7, 52). This modification, even
at the level of a single amino acid, may be
enough to cause oncogenic transformation
without increased expression of the oncogene
(52). DNA tumor viruses may act in a similar
way by integrating their DNA into control
regions allowing expressions of normally re-
pressed genes or, alternatively, may add infor-
mation into non-control regions which, when
expressed, leads to the neoplastic phenotype.
2. Modulation of DNA Damage and Repair.
A considerable body of data exists on DNA
damage and repair in isolated DNA, bacteria,
cell cultures, isolated cells, tissue slices, and in
vivo (37, 60). However, by use of certain in
vitro assay systems measuring DNA damage
and repair, important factors operating in the
whole animal are neglected. These include
circulatory dynamics, changing blood constitu-
ents such as hormones, mitotic rate, cell type
differences, stage of differentiation, hypoxia,
membrane transport, biological rhythms, and
xenobiotic metabolism. A number of studies,
described below, illustrate the effect of these
factors on DNA damage and repair in vivo.
The rate and extent of repair of ethylnitrosou-
rea, methylnitrosourea, and dimethylnitrosou-
rea-induced Oe-deoxyguanosine alkylation is
decreased dramatically in target tissues of the
rat when compared to nontarget tissues (22,
34). Induction and rejoining of y-ray induced
strand breaks in mouse testicular cells are less