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OCR for page 135
3
Mechanisms of Radiation-Induced Cancer
}lACKGROUND
Carcinogenesis is viewed as a multistep process in which two or more
intracellular events are required to transform a normal cell into a cancer
cell. The concept that carcinogenesis involves more than one step is derived
from three main lines of evidence: (1) the rate of mortality from cancer
increases as a power function of age, (2) a long latent period typically
intervenes between exposure to a known carcinogen and the appearance of
cancer, and (3) three distinct and separate stages have been identified in
experimental carcinogenesis: initiation, promotion, and progression.
The fact that the cumulative incidence of cancer increases approx-
imately as the seventh power of age during adult life prompted early
investigators to postulate the existence of seven successive events, or steps,
in the conversion of a normal cell into a cancer cell; these events were
thought to involve mutational changes in the broadest sense (Arson. This
concept failed to recognize, however, the high rates of somatic mutation
that such a seven-stage model would require, the dynamic state of the target
cells, and the peculiar age distributions typical for the cancers occurring
during childhood. If the kinetics of target cells and the possible growth ad-
vantage of preneoplastic cells are taken into account, the age distributions
of pediatric and adult cancers can be explained in terms of just two rate-
limiting mutational steps (e.g., see Mo81), although other events that might
be associated with tumor progression or tumor metastasis are not excluded.
In a tumor that has grown to a population of 106 cells, even events that
occur only rarely in each cell division can be expected to occur with a high
135
OCR for page 136
136 EFFECTS OF EXPOSURE TO LOW LE^LS OF IONIZING MOTION
probability in the total cell population. Models that account for all of the
complex factors involved in the mechanisms of carcinogenesis have not yet
been developed to the point where they can be used realistically for risk
estimation, especially in view of the fact that the sparsity of data available
makes it difficult to choose among the various possibilities. In Chapter 4
of this report, therefore, descriptive empirical models are used to arrive at
cancer risk estimates.
MECHANISMS
The mechanisms by which radiation may produce carcinogenic changes
are postulated to include the induction of: (1) mutations, including alter-
ations in the structure of single genes or chromosomes; (2) changes in
gene expression, without mutations; and (3) oncogenic viruses, which, in
turn, may cause neoplasia. Although controversy persists as to the relative
importance of these hypothetical mechanisms in the induction of carcino-
genesis, they are not mutually exclusive, since different mechanisms may
be involved at successive stages in carcinogenesis.
The somatic mutation theory of carcinogenesis, proposed by Boveri
in 1914 (Bol4), has received further support from the high correlation
between the carcinogenicity and the mutagenicity of different agents. In
a few types of cancer (e.g., retinoblastoma), moreover, the same specific
gene mutation or deletion is found both in familial and nonfamilial cases,
as noted in Chapter 1, suggesting that the mutation or the deletion of the
gene plays a causative role, as discussed below.
It is possible, on the other hand, that premalignant or malignant
alterations do not necessarily result from changes in gene or chromosome
structure per se, but from changes in gene expression. Support for this
concept comes from evidence that nuclei transplanted from cancer cells into
enucleated ova or blastocysts can produce apparently normal organisms or
tissues in various species, including mice (Brew. Nevertheless, altered gene
expression does not exclude the possibility that premalignant cells might
undergo mutation during their conversion to cancer cells.
Initiation, Promotion, and Progression in Carcinogenesis
The following generalizations about the process of carcinogenesis are
noteworthy: (1) The effects of radiation and chemical carcinogens which
lead to cancer are dose dependent and generally irreversible; (2) the
carcinogenic process is dependent on cell proliferation; (3) the changes
that initiate carcinogenesis in a cell are passed on to daughter cells; (4)
the subsequent events in carcinogenesis can be profoundly influenced by
various noncarcinogenic factors; and (5) tumors tend to become increasingly
OCR for page 137
MECHANISMS OF RADL4TION-INDUCED CANCER
137
malignant with time through the stepwise outgrowth of progressively more
malignant subpopulations of tumor cells.
It is now widely accepted that initiation, the first step in malignant
cell transformation, begins the carcinogenic process, while in most cases
promotion is required to complete the process (Comb. This concept of
carcinogenesis as a two-stage process was suggested originally by studies of
tumor induction in mouse skin in which a dose of chemical carcinogen that
was too small to cause a detectable increase in the incidence of tumors
was found to induce a high incidence of tumors if it was followed by
repeated administration of a suitable promoting agent, an agent that did
not cause tumors when administered alone (Bo74a, Beam. A synergistic
interaction between the initiating effects of radiation (or various chemicals)
and specific promoting agents is now known to occur in many different
organs and cell-systems (Mo64, Pe85, Ja86, Ke84a). In these studies, it
was observed that promotion caused a higher incidence of cancer with a
shortened latent period (Ryan. It has been widely assumed that a similar
two-stage mechanism involving initiation and promotion exists for radiation
. .
carclnogenesls.
Whereas most initiating agents, including radiation, are carcinogenic
by themselves in a single exposure if they are administered in a sufficiently
large dose, promoting agents must be given repeatedly over long periods of
time, during which successive phases of promotion may be distinguishable
(Peats. Different promoting agents, moreover, may act at different stages
of promotion. By the same token, different agents that inhibit promotion
may act at different stages in the process (Pearl.
The term tumor progression has been used traditionally to denote
the acquisition of increasingly malignant properties within an established
cancer, presumably via genetic instability. However, the term has also
come to be used to denote the conversion of a benign growth into a
malignant growth. In either case, the process reflects the proliferation of a
subpopulation of cells within a tumor. This subpopulation of cells expands
and overgrows the less aggressive cells. Radiation has been shown to be
capable of enhancing the process of progression (Jamb. Other clastogenic
agents such as hydroxyurea (Hah86) may also be progression agents for
carcinogenesis (Personal Communication, Dr. Henry Pitot). Similarly,
initiation-promotion-initiation experiments, in which promotion is followed
by a second initiation step brought about by the administration of an
initiator, have been found to increase the final incidence of malignant, as
opposed to benign tumors (Most, He83~. While initiation is thought by
some investigators to result from mutational events, promotion appears to
involve non-mutational effects on the kinetics of intermediate-stage cells.
The first step in the initiation of carcinogenesis, whether by radiation
or a chemical carcinogen, has been observed to be an event that occurs
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138 EFFECTS OF EXPOSURE TO LOW LE^LS OF IONIZING MOTION
in a large percentage of treated cells (Ke85a, C186a, C186b, Wages. The
frequency with which this event can be produced experimentally far exceeds
the frequency of mutations at any one gene locus, contradicting the notion
that the initiating event is a specific single-locus mutation. Instead, initiation
more likely appears to be an event that increases the genomic instability
of the cells in subsequent rounds of cell division (C186b, Wage, Ke84b).
Although much experimental data has suggested that the first event in
radiation and chemical carcinogenesis is a widespread, nonmutagenic type
event, the same data has suggested that later events in the carcinogenic
process appear to behave like mutations. Thus the notion that mutagenic
events may occur in carcinogenesis still has widespread support, as indicated
elsewhere in this report.
The hypothesized high-frequency initiating event could conceivably be
a change in gene expression (for example, see Fa80) of a type that might
occur in a large proportion of irradiated cells (Sc854; in Eschenchia coli, for
example, radiation induces an error-prone DNA repair system (the SOS
system) which leads to mutations that would otherwise occur only rarely"
(Wimp. Although the SOS system is activated for only a short period of
time, other radiation-induced systems may be activated for longer peri-
ods; for example, recombinational events in yeast continue to occur for
many generations after irradiation (Fame. In this connection, it is note-
worthy that SOS functions are also activated by a protease (Li80a) but are
suppressed by protease inhibitors (Me77), which also suppress radiation-
induced recombination in yeast (Wi84) and radiation-induced malignant
cell transformation in vitro (Ke85b). Many other agents that enhance
or suppress carcinogenesis in vivo exert similar effects on malignant cell
transformation in vitro (Ke84a); these include retinoids (vitamin A deriva-
tives), antiinflammatory steroidal agents, antioxidants, vitamins, protease
inhibitors, and other substances (S180, Pe85, Wa85, Ke84a).
After exposure to a carcinogen, proliferation of the exposed cells is
essential to their subsequent neoplastic transformation. Tissue irritation,
which stimulates cell division, was recognized long ago to increase the prob-
ability of tumor development; for example, following carcinogen treatment
of the skin or liver, wounding of the skin or partial hepatectomy enhances
tumor formation in the skin or liver, respectively (Sump. Similarly, the
carcinogenic effects of memo alpha radiation on the lung of the hamster are
enhanced by repeated instillation of saline into the airway, which stimulates
proliferation of pulmonary epithelial cells (Li78, Sham. Likewise, cigarette
smoke, which contains small amounts of many known carcinogenic agents
(such as Hippo) and which is a potent irritant, appears to potentiate the
effects of inhaled radon and its daughter products in uranium miners (Lo44,
Lu71, Sadly. Proliferation is thought to play a role in the fixation of radia
OCR for page 139
MECHANISMS OF RADIATION-INDUCED CANCER
139
lion damage which leads to malignant transformation in the expression of
that damage and in the promotional phase of cancer development.
The mechanism of tumor promotion is still obscure. Promoters such as
phorbol esters are known to interrupt intercellular communication in some
cell populations (1182), and they have traditionally been thought to be
nonmutagenic (Ma83) and thus to act through effects on gene expression
(Bomb. Recently, however, some such agents have been found to pro-
duce chromosome aberrations (Em81), aneuploidy (Pa81), sister chromatic
exchanges (Ki78, Na79), and single-strand breaks in DNA (Bight. Many
promoting agents, moreover, induce free radicals in cells (Go81, Fight.
These free radicals can, in turn, damage DNN It is noteworthy, therefore,
that free radical-generating agents can act as tumor promoters (Ke86) and
that inhibitors of free radical reactions can suppress tumor promotion in
some systems (S183~.
Radiation itself also can enhance tumor promotion, tumor progression,
and the conversion of benign growths to malignant growths (Jamb. ~ the
extent that the effects of radiation are mediated by free radicals (Li77),
which can also mediate the effects of promoting agents (Co83), sequen-
tial exposures to radiation may serve to promote tumorigenesis through
mechanisms similar to those of chemical promoting agents.
Natural hormones also may promote carcinogenesis in irradiated indi-
viduals. However, it is not yet clear how comparable the effects of hormones
are compared to the effects of the classical promoting agents. Hormonal
promotion conceivably may be mediated through physiological effects on
the proliferation and differentiation of cells (~186a,b, Wages. It may also
be mediated through autocrine growth factors or their receptors, such as
those that may be under the influence of certain oncogenes (Spew. In
some cases, hormones may actually suppress tumor promotion by inducing
differentiation in cells that are at risk
Other factors capable of having a highly significant effect on the various
stages of carcinogenesis include age, sex, genetic constitution, capacity
to repair DNA, carcinogen metabolism, immunologic status, and dietary
factors such as caloric intake (Sump.
Radiobiological Factors Affecting Oncogenic lYansfo~mation
During the past two decades, much information has been gathered
about radiation carcinogenesis from experimental systems in which cul-
tured mammalian cells are transformed to a malignant state by exposure to
radiation. In vitro transformation assays have been used extensively to study
the carcinogenic effects of radiation in a highly quantitative fashion and in
a defined environment. One major advantage of such in vitro systems is
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140 EFFECTS OF EXPOSURE TO FOW LE^LS OF IONIZING MENTION
that the effects of radiation on specific target cells can be studied directly
without the presence of extraneous factors, which complicate carcinogenesis
in viva. In addition, transformation assays are extremely sensitive, allowing
detection of the carcinogenic effects of radiation at doses below those at
which statistically significant carcinogenic effects have been observed in
animal and human studies. It has been observed by many investigators that
radiation-induced transformation in vitro can be modified in the same way
as radiation-induced cancer in animals, with the yields of malignant cells
varying similarly in response to different characteristics of the radiation
(such as total dose, dose rate, fractionation pattern, linear energy transfer
(LET), etc.) and many other modifying factors, as described below. It is
widely inferred that the processes involved in radiation-induced transfor-
mation in vitro are similar to those involved in carcinogenesis in viva, and
that results from in vitro studies are applicable to radiation-induced cancer
in vivo. In vitro transformation systems also offer an approach to studying
radiation carcinogenesis that is less expensive and less time-consuming than
animal experiments.
Dose Response
Commonly used in vitro transformation assays can be divided into two
broad classes. First, there is the use of short-term cultures of embryo cells,
with clonal assays in which transformed clones can be identified after an
incubation period of about 14 days. The transformation frequency and the
surviving fraction can then be assessed from the same culture dishes.
Second, there are assays with established cell lines (such as 3T3,
lOTl/2, Rat 2) that have become immortal. These are focal assays, and for
transformed foci to become identifiable, the culture must be continued for
some weeks after the normal cells have reached confluence. Cell survival
and transformation frequency cannot be assessed from the same culture
dishes. Results can be expressed as transformation frequency per surviving
cell, but because the transformation frequency observed is a function of
the number of viable cells seeded per culture dish, the data can also be
expressed in terms of the number of foci per dish or the fraction of culture
dishes bearing foci.
These in vitro assays, based on rodent fibroblasts, have been used
widely because they are highly quantitative. Ideally, assays based on human
epithelial cells would be more relevant, but, although transformation in
human cells has been demonstrated as a result of exposure to radiation or
chemicals, quantitative assays are not available.
In recent years, in viva transformation assays also have been developed
for thyroid and mammary cells in rats. Cells are irradiated in situ in the
thyroid or mammary gland and are subsequently excised and transplanted
OCR for page 141
MECHANISMS OF RADIATION-INDUCED CANCER
1 Do C 7:~
o
o
IL
cn
By
~ 1 0 '
o
A:
10-1
m
m 10-4
o
cat
o
10 T 1/2 CELLS
in_
-
Survival
/
/\< 100 rad/min
60Co y- rays
Transformation ~
(per cell exposed) `\
\\ Do = 150 red
\
i/
/~
0 200 400 600
141
800 1000 1200 1400 1600 1800
DOSE (red)
FIGURE 3-1 Probability of survival (top) and transformation per
as a function of dose (Hangs.
· I]
rradiated cell (bottom)
to a fat pad in a suitably prepared animal. Cell survival and transformation
incidence can be determined in this way (C186a, C186b). Experiments using
different initial cell densities or reseeded/diluted cell cultures have indicated
that the malignant transformation of cells arises from very few carcinogen-
treated cells (Ke85a, C186b). These results have led to the notion that the
first event in carcinogenesis is a high frequency event as discussed earlier.
The dose-response relationship for the induction of radiogenic trans-
formation reflects a balance between an increase with dose in the pro-
portion of cells that are transformed and a decrease in cell survival. This
is illustrated in Figure 3-1 (Hades. For gamma rays and other low-LET
radiations, the cell survival curve is characterized by a broad initial shoulder
OCR for page 142
142 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION
region before it becomes steeper and approaches an exponential function
of dose at higher doses (Figure 3-1) (Hash. Transformation incidence, as
expressed by frequency per surviving cell, increases with dose up to a few
Gray, and reaches a plateau at higher doses. While the transformation
data are often plotted in terms of frequency per surviving cell, they can
also be expressed as frequency per initial cell at risk when applying these
in vitro data to whole organisms. This approach is also illustrated in Fig-
ure 3-1 where the dose-response transformation curve rises at low doses,
reaches a maximum, and falls at higher doses to eventually parallel the
cell-killing curve. The curve represents a balance between transformation
and cell killing and indicates that cells destined to become transformed
have a survival response similar to that of untransformed normal cells. The
peak of the dose-response curve for transformation frequency per initial
cell at risk often reaches higher values for densely ionizing radiations, such
as neutrons and alpha particles than for x rays or gamma rays.
Dose Rate and Dose Fractionation
For low-LET radiations, the consensus is that cell survival is enhanced
by a decrease in the dose rate or separation of the dose into a number of
fractions. Effects on the yield of transformants, however, are more complex.
It has been reported that for low-LET radiations, splitting or fractionating
the dose or reducing the dose rate can either enhance (Bo74, Ha81, Li79)
or decrease (Hi84) the transformation frequencies in a variety of in vitro
transformation models. More recent studies suggest that the proliferative
status of the cells may account for some of the observed variation (Lump.
Using C3HlOTl/2 cells, Hill et al. (Hi85) have compared dose-response
transformation curves for gamma rays and for fission spectrum neutrons
delivered in both a single exposure or in multiple small fractions. Although
fractionation was observed to result in a sparing effect on transformation
by gamma rays, it increased the rate of transformation by fission spectrum
neutrons (Ha79, High. Since enhanced transformation was observed after
exposure to multiple low doses or a continuous low dose rate, compared
to high-dose-rate fission spectrum neutrons, the relative biological effec-
tiveness (RBE) of neutrons relative to that of gamma rays was larger at
low-dose rates than at high-dose rates. As outlined in chapter 1, these
observations have important practical implications for the selection of an
appropriate RBE for neutrons.
Linear Energy Transfer (LET)
Comparisons of various high- and low-LET ionizing radiations for
their abilities to induce oncogenic transformation in several cell systems
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MECHANISMS OF RADIATION-INDUCED CANCER
143
have been reported. In general, high-LET radiations are far more cytotoxic
and oncogenic than low-LET radiations such as x rays or gamma rays.
Furthermore, the RBE for oncogenic transformation and pytotoxicity in-
creases with increasing LET of the radiation. Hence, if the transformation
frequencies for each type of high-LET particle are plotted against the cor-
responding survival values, the curves obtained cannot be superimposed.
This suggests that there is a real difference in the RBE between cell killing
and transformation (He88, Ya85) and also indicates that there is a signifi-
cant frequency of transformation at doses of high-LET radiations that have
very little effect on cell survival.
Figure 3-2 JIa87a) shows survival and transformation data for gamma
rays and high-LET helium-3 ions. The cell survival curve for gamma rays
has a broad initial shoulder, while that for helium-3 ions is an exponential
function of dose. For high-LET particles, the transformation frequency
peaks at a much lower dose than for gamma rays and reaches a value that
is higher by a factor of about 5 than is the case for gamma rays (Ha87a).
Neutrons are also highly effective at inducing transformation. Figure
3-3 shows the variation of RBE with neutron energy over a wide range,
1.0
0.01
~ He3 ions ~Forays
Surviving Fraction ~
i\
~0.1 \; ~\
.g -/\ Transformants per I/\
~:1` \ Surviving Cell 7 ~\
c~ ~ i\
- W
Transformants
per Cell at Risk
0.001 ~
t;-~
1 1 1 _
2 o 2 4 6 8
Transforrnants pert
Cell at Risk
Dose (Gy) Dose (Gy)
110 -2
\
\
l
10
10-3 ~
a)
IL
O
._
Is
~0
10-4
10-5
FIGURE 3-2 Cell survival curves and dose response relationships for oncogenic trans-
formation for C3HlOT1/2 cells irradiated with either gamma rays or high-LET helium-3
ions. Itansformation frequencies are expressed in two ways; per surviving cell and per cell
initially at risk (Ha87a).
OCR for page 144
144 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING IDEATION
40
30
UJ ^^
m en
it
10
o
· Survival
· Transformation
_ _ I ~
I_ _
1o2
103
Neutron Energy (keV)
104
FIGURE 3-3- RBEm for cell cu~vinal and for oncogenic transformation as a function of
neutron energy and C3HlOT1/2 cells irradiated with monoenergetic neutrons (Might.
which is similar to that received by individuals during the bombing of
Hiroshima (Mi894. Energies of about 350 kiloelectron volts (keV) are most
effective for both cell lethality and transformation. There is evidence that
the effectiveness of neutrons increases with a decrease in the dose rate. As
a consequence of this, RBE values are higher for a fractionated or a low-
dose-rate exposure, than for a single, brief exposure, as mentioned above.
It has been suggested that the misrepair of sublethal radiation damage in
fission neutron-irradiated cells may account for the increased RBE values
(Highs.
Alpha Particles
The transforming ability of alpha particles also has been studied ex-
tensively with in vitro transformation systems. Robertson et al. (Ro83)
showed that the RBE for transformation by plutonium-238 alpha parti-
cles in Balb/3T3 cells was substantially higher than that for cell lethality.
It was also demonstrated that potentially lethal damage was repaired in
x-irradiated 3T3 cells and was not repaired in alpha-particle irradiated
cells, resulting in a high RBE value for oncogenic transformation in alpha-
irradiated plateau-phase cultures.
Similar findings have also been reported by Hall and Hei who used
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MECHANISMS OF RADIATION-INDUCED CANCER
145
the C3HlOTl/2 cell system (Ha85). At equivalent doses, alpha particles
were substantially more cytotoxic than gamma rays and were more efficient
in inducing oncogenic transformation. The calculated RBE value for alpha
particles ranged from 2.3 to 9 over the range of doses studied, with the
highest RBE value at the lowest dose. Recent results have suggested the
absence of a dose-rate effect with alpha particles (Highs.
Previous studies by Lloyd et al. (L179) showed that at a dose corre-
sponding to a surviving fraction of 37%, about 14 particles traversed the
nucleus for each cell killed. The fact that on the average 13 particles
may traverse a cell nucleus without killing the cell may explain the high
efficiency with which high-LET particles induce transformed loci.
Agents That Modify Radiation Transformation
Many different classes of agents have been shown to modify radiation-
induced transformation in vitro (Ke84a). The tumor promoting agent 12-0-
tetradecanoyl phorbol acetate (TPA) has been studied in many laboratories
for its ability to enhance radiation-induced transformation. It is of particular
interest that promoting agents such as TPA can change the shape of the
dose-response curve for radiation-induced transformation, making it linear
(Figure 3-4) (Kemp. This alteration of the dose-response relationship also
occurs in promotion by TPA of radiation carcinogenesis in vivo (Figure 3-
5) (Freer. While promotion can greatly enhance radiation transformation,
other agents can suppress radiation transformation or the enhancement
by TPA (Kemp. An example of the suppressive effect of the protease
inhibitor antipain on radiation transformation and the TPA enhancement
of radiation transformation is shown in Figure 3-6. Other examples of
agents which suppress radiation transformation are selenium (Figure 3-
7), which is thought to exert its inhibitory action by inducing glutathione
peroxidases, and 5-aminobenzamide, which is an inhibitor of poly-ADP-
ribose synthetase.
The frequency of transformation resulting from a given dose of ra-
diation can also be modulated by the level of thyroid hormone in the
serum. With high levels of T3 hormone (corresponding to hyperthyroid
conditions) the transformation incidence resulting from 3 Gray of x rays
is increased, while with low levels of T3 hormone, (corresponding to hy-
pothyroid conditions), the transformation incidence is not detectable above
the spontaneous level. The suppressing effects of some of these agents are
illustrated in Figure 3-7 (Ha87a).
GENETICS OF CANCER
As noted above, much evidence supports the concept that mutation is
involved in the etiology of cancer. Recent research has identified critical
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150 EFFECTS OF EXPOSURE TO LOW LE^LS OF IONIZING MOTION
search for the responsible gene. Genetic linkage studies have shown that
the heritable cases without a deletion involve a mutation at the same site.
Although carriers of the mutation develop a mean of three to four
tumors, the inherited mutation alone is not sufficient for the production of
the cancer; another event is necessary. The second event that is necessary
is the loss or mutation of the normal allele on the other chromosome 13 by
nondisjunction, deletion, genetic recombination, or local mutation (Ca82,
Knew. The result in all cases is the same: the tumor cell contains no
normal copy of the retinoblastoma gene. Hence, although inheritance of
the predisposition is dominant, oncogenesis at the cellular level is reces-
sive. Therefore, the normal allele can be viewed as protective, thus, the
designation tumor-suppressor gene, or antioncogene.
Patients with retinoblastoma have a high risk of developing osteosar-
coma of the orbit following radiation therapy. They also have a lesser
predisposition to osteosarcoma in the absence of irradiation. In either
case, the genetic change in the tumor cells is the loss of the two normal al-
leles of the retinoblastoma gene; thus, this gene is a tumor-suppressor gene
for osteosarcoma (Ha85) as well as for retinoblastoma. The probability of
mutation or loss of the normal gene in persons born with one mutant gene
in the germ line is apparently increased by radiation, as would be expected.
The retinoblastoma gene has recently been cloned, an accomplishment
that will greatly facilitate investigation of the relevant oncogenic mechanism,
the identification of those at risk, and the study of the physiology of the
gene in normal development (Fr86a, Fu87b, Le87a, Le87b). It has already
been shown that the messenger RNA (mRNA) of the gene is absent or
defective in virtually every case of retinoblastoma, whether it was inherited
or not. In the nonhereditary cases, the two normal genes are lost or
mutated as the result of two somatic events, the second events being of
the same kinds as those observed in heritable cases (see above). The only
difference between the two forms of tumor is that the first event is present
in the germ line in one form and occurs after conception in the other.
The idea that recessive genes may suppress the oncogenic process is
not new. Previous experiments with somatic cell hybrids have shown that
the neoplastic character of most tumor cells can be suppressed by fusing
the cells with normal cell partners (Stem. On the other hand, it is clear
that oncogenes are frequently abnormal in structure and/or function in
many tumors. It is probable, therefore, that protooncogenes and tumor-
suppressor genes are both important in carcinogenesis. Whether either or
both are necessary in every case of cancer remains to be determined.
Recessive Breakage and Repair Disorders
These disorders, which include xeroderma pigmentosum, ataxia telang-
iectasia, Fanconi's anemia, and Bloom's syndrome, are recessively inherited
OCR for page 151
MECHANISMS OF RADIATION-INDUCED CANCER
151
conditions that predispose the chromosomes of an individual to breakage
and/or defective repair of DNA damage (Hansel. They do not involve
cancer genes of the types discussed above but can be viewed as conditions
that increase the probability of a cancer-producing mutation.
Thus, in xeroderma pigmentosum a defect in excision repair permits
an increased rate of mutations at all genetic loci in cells exposed to sunlight.
Ataxia telangiectasia predisposes the chromosome to breakage, especially in
lymphocytes; the underlying molecular defect is not known, but it is thought
to involve a defect in DNA repair. Patients with the syndrome are especially
predisposed to lymphoid neoplasia, and their cells are highly sensitive to
ionizing radiation. Chromosome breakage and rearrangement are regular
features of Fanconi's anemia, which predisposes an individual to acute
myelomonocytic leukemia; the underlying molecular defect for this is not
known. Finally, Bloom's syndrome is associated with high rates of mutation
and of sister chromatic, and even homologous chromosome, exchanges.
The molecular defect apparently involves a ligase that is important in
the repair of DNA damage (Ch87, Wield. The syndrome predisposes an
individual to several kinds of neoplasia, perhaps by facilitating mutation,
somatic recombination, and the expression of recessive oncogenes.
Genetic Polymorphism for Metabolism of Carcinogens
In contrast to the aforementioned DNA repair disorders, in which the
response to an environmental agent is altered, there are cases in which
the response may be normal but the amount of radiant energy imparted is
increased. Thus, albinos are sensitive to ultraviolet light because they absorb
more of it, not because they have a defective DNA repair mechanism.
Such a genetic predisposition is also known for many chemical carcinogens
(Ca82, Ko82, Ay84, Goofy. Hence, to the extent that the effects of
a given chemical may promote the carcinogenic effects of radiation, traits
affecting the metabolism of the chemical may alter susceptibility to radiation
. .
carcmogenesls.
Hereditary Fragile Sites
Another kind of inherited mutation that may predispose an individual
to cancer is the hereditarily fragile genetic site. About 18 such sites are
known. Fragility for a specific site can be elicited in vitro, and the fragility
is transmitted in a Mendelian dominant fashion (Hemp. Although several
of the sites have been found to be situated at or near break points that are
known to be involved in various cancer-associated translocations (Le84),
cancer does not appear to be common in families with such abnormalities.
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152 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING EDITION
The importance of these mutations in carcinogenesis thus remains to be
determined.
EFFECTS OF AGE, SEX, SMOKING, AND OTHER SUSCEPTIBILITY
FACTORS
As discussed in the preceding section, the carcinogenic process includes
the successive stages of initiation and promotion. The latter phase, pro-
motion, appears to be particularly susceptible to modulation, with cigarette
smoking being a conspicuous example of a modulating factor. Susceptibility
to the carcinogenic effects of radiation can thus be affected by a number
of factors, such as genetic constitution, sex, age at initiation, physiological
state, smoking habits, drugs, and various other physical and chemical agents
(UNBID. The mechanisms through which these factors influence suscepti-
bility are, however, not well understood. Moreover, they depend on the
particular type of cancer, the tissue at risk, and the specific modifying
factor under consideration. Therefore, the Committee elected to discuss
the factors affecting carcinogenesis at specific organ sites in Chapters 4 and
5.
Some general conclusions can be drawn from the observations reported
in Chapter 4. Cancer rates are highly age dependent and, in general,
increase rapidly in old age. The expression of radiogenic cancers varies
with age in a similar way, so that the age-dependent increase in the excess
risk of radiogenic cancer is conveniently expressed in terms of relative risk;
that is, the increased risk tends to be proportional to the baseline risk
in the same age interval. In some cases, however, such as breast cancer,
the change in the baseline cancer rate with age is more complicated and
possibly related to variations in hormonal status with age. Susceptibility to
radiation-induced breast cancer may be similarly complicated, as outlined
in Chapter 5, and there is some indication that protective factors for breast
cancer in nonirradiated women, such as early age at the birth of the first
child, may also be relevant for radiation-induced breast cancer.
The situation is less clear for the risk factors for lung cancer. The
BEIR IV Committee found that smoking and prolonged exposure to in-
haled alpha-particle emitters interacted in a multiplicative fashion, or nearly
so, with the result that the increased risk of radiogenic lung cancer in those
of a given smoking status was proportional to the baseline risk for the
same smoking status (NRC88~; however, this may not be the case for acute
exposures to x rays and gamma rays. It is commonly believed that the data
on lung cancer and smoking among the atomic-bomb survivors support
an additive risk model, in which there is no interaction between radiation
and tobacco use. Nevertheless, the BEIR IV Committee's analyses of these
OCR for page 153
MEClIANISMS OF REDLY TION-INDUCED CANCER
153
data indicated that the pattern of observed risk is also compatible with
a multiplicative interaction. Currently, available data are ambiguous, as
indicated in Chapter 5, and further studies are needed to explore the role
of cigarette smoking as a risk factor for radiation-induced cancer.
For lung cancer and most other non-sex-speciSc solid cancers, it is
unclear how a person's sex affects the risk of radiogenic cancer. In general,
baseline rates for such cancers in males exceed those in females, possibly
because of increased exposure to carcinogens and promoters in occupa-
tional activities and life-style factors, such as increased smoking and use of
alcohol. While sex specific excess rates of cancer can generally be modeled
adequately as being proportional to the corresponding sex-specific baseline
rates, in many cases an additive excess risk model fits the data equally well;
that is, the number of radiation-induced cancers per unit dose is nearly
the same in both sexes. This means that the relative-risk coefficient for
females compared with that for males is, to a good approximation, inversely
proportional to the ratio of the sex-specific baseline rates (NRC88~. For
this reason, as outlined in Chapter 4 and in Annex 4D, the Committee
tested a number of risk models that include sex as a modifying factor for
the risk of radiogenic cancer.
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Representative terms from entire chapter:
radiation transformation
