Læknablaðið - 15.10.1983, Blaðsíða 32

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LÆKN ABLADID
than in other cells, an effect attributed to
hypoxia in situ (51). Aflatoxin B, (AFBj)
binding to rat liver DNA is reduced 70-90 %
by pretreatment with phenobarbital (70), and
hypophysectomy reduces AFB, binding by
50 % (70). Both treatments also reduce the
tumorigenicity of AFB!. This effect of hypop-
hysectomy may suggest the existence of other
neuro-hormonal effects on DNA damage,
DNA repair, and carcinogenesis in vivo. Bind-
ing of 7,12-dimethylbenzanthracene (DMBA)
to rat mammary DNA is highest at 50 days,
the age of highest tumor susceptibility (31).
The proliferative state of a tissue can
determine whether a given compound will be
carcinogenic. Rat liver tumors can be induced
by a single dose of dimethylnitrosamine in
neonates but only following partial hepatecto-
my in the adult animal (49). Chronic doses of
dimethylnitrosamine, present for a longer time
than the cell turnover time, are hepatocarci-
nogenic even in the adult (49). Differentiation
also affects DNA repair in vivo. Sega (64) has
shown that repair of ethylmethylsulfone
(EMS) damage decreases with differentiation,
as mouse spermatocytes mature into sperma-
tids. The time of loss of repair capacity
coincides with the time of appearance of
dominant lethal mutations. Ono and Okada
(51) found a similar yradiation repair profici-
ency in rat spermatogonia, with complete loss
of repair activity in spermatozoa.
Thus, numerous endogenous and exogenous
factors appear to affect DNA repair in vivo.
The extent to which these factors may be
accounted for in the extrapolation of DNA
damage and repair data from in vitro to in
vivo systems is unknown. Also the impact of
these in vivo alterations in the DNA repair
system on the ultimate induction of tumors
remains to be clarified. This problem is even
further complicated by the more recent obser-
vation that chemical and physical carcinogens,
when given in combination with one another
(chemical-chemical, chemical-physical, or phy-
sical-physical), may inhibit or enhance the
repair of DNA damage induced by each
separate factor (1, 3, 53). It therefore appears
that DNA damage does play a role in the
induction of cancer. However, few methods
exist to measure such damage in vivo. This
puts limitations on the extrapolation from in
vitro data to in vivo effects, due partially to
many factors, both external and internal, that
modulate DNA repair in vivo.
It is well established that differences in
DNA repair exists between both animal stra-
ins and organs as well as species (11, 12). This
is illustrated in studies by Sheikh et al (65) on
the in vivo DNA binding of DMBA in
Sprague-Dawley and Long-Evans rats. The
DNA binding profiles of DMBA in five organs
(kidney, lung, heart, mammary gland, and
liver) were determined over a seven day
period. The maximum binding levels were two
to eight times higher in all organs of the Long-
Evans strain when compared to those of
Sprague-Dawley. In Long-Evans rats, lung
had the highest binding level, followed by
heart and mammary gland. In Sprague-Daw-
ley rats, liver had the highest binding. The rate
of removal of adducts was consistently greater
in the Long-Evans strain of rats when compa-
red to that in Sprague-Dawley rats. All the
organs of the Long-Evans rats had lost at least
90% of their DMBA modified adducts seven
days post-treatment whereas in all organs of
Sprague-Dawley rats, with the exception of
liver, only 9 to 43 % of the adducts were lost.
Livers of both Sprague-Dawley and Long-
Evans rats excised relatively large amounts of
adducts. Consistent with these findings is the
observation of Huggins et al (28), which
established that administration of DMBA (10
mg/day/i.g.) to young female Sprague-Dawley
rats produced a 100 % incidence of mammary
cancer whereas the same dose produced only
30 % incidence in Long-Evans animals. Thus,
the results of Sheikh et al (65) suggest that the
relatively greater resistance of the Long-
Evans strain to mammary carcinogenesis is a
function of repair processes rather than abso-
lute binding.
A single atom modification of a carcinogen
can make a difference with respect to the
carcinogepic effect and this is reflected not
only in metabolism and binding, but also in
repair (14). For example, the highest binding
level of 2-fluoro-DMBA is only 3 to 10% of
that found with DMBA in all tissues studied in
Sprague-Dawley rats. The rates of excision of
2-fluoro-DMBA-modified adducts from the
DNA of the heart, mammary and liver tissues
of Sprague-Dawley rats were higher than
those observed for DMBA. The lower level of
adduct formation with 2-fluoro-DMBA and