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National Research Council (US) Committee on the Biological Effects of Ionizing Radiation (BEIR V). Health Effects of Exposure to Low Levels of Ionizing Radiation: Beir V. Washington (DC): National Academies Press (US); 1990.

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Health Effects of Exposure to Low Levels of Ionizing Radiation: Beir V.

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3Mechanisms of Radiation-Induced Cancer


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 approximately 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 (Ar54). 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 advantage 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 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.


The mechanisms by which radiation may produce carcinogenic changes are postulated to include the induction of: (1) mutations, including alterations 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 carcinogenesis, 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 (Bo14), 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 (Br77). 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 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 (Co83). 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, Be75). 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 (Ry71). It has been widely assumed that a similar two-stage mechanism involving initiation and promotion exists for radiation carcinogenesis.

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 (Pe85). 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 (Pe85).

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 (Ja87). 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 (Mo81, 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 in a large percentage of treated cells (Ke85a, Cl86a, Cl86b, Wa88). 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 (Cl86b, Wa88, 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 (Sc85); in Escherichia coli, for example, radiation induces an error-prone DNA repair system (the SOS system) which leads to mutations that would otherwise occur only rarely (Wi76). Although the SOS system is activated for only a short period of time, other radiation-induced systems may be activated for longer periods; for example, recombinational events in yeast continue to occur for many generations after irradiation (Fa77). In this connection, it is noteworthy 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 derivatives), antiinflammatory steroidal agents, antioxidants, vitamins, protease inhibitors, and other substances (Sl80, 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 probability 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 (Su73). Similarly, the carcinogenic effects of 210Po 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, Sh82). Likewise, cigarette smoke, which contains small amounts of many known carcinogenic agents (such as 210Po) and which is a potent irritant, appears to potentiate the effects of inhaled radon and its daughter products in uranium miners (Lo44, Lu71, Sa84). Proliferation is thought to play a role in the fixation of radiation 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 (Tr82), and they have traditionally been thought to be nonmutagenic (Ma83) and thus to act through effects on gene expression (Bo74). Recently, however, some such agents have been found to produce chromosome aberrations (Em81), aneuploidy (Pa81), sister chromatid exchanges (Ki78, Na79), and single-strand breaks in DNA (Bi82). Many promoting agents, moreover, induce free radicals in cells (Go81, Fi85). These free radicals can, in turn, damage DNA. 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 (Sl83).

Radiation itself also can enhance tumor promotion, tumor progression, and the conversion of benign growths to malignant growths (Ja87). To the extent that the effects of radiation are mediated by free radicals (Li77), which can also mediate the effects of promoting agents (Co83), sequential 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 individuals. 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 (Cl86a,b, Wa88). It may also be mediated through autocrine growth factors or their receptors, such as those that may be under the influence of certain oncogenes (Sp85). 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 (Su73).

Radiobiological Factors Affecting Oncogenic Transformation

During the past two decades, much information has been gathered about radiation carcinogenesis from experimental systems in which cultured 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 that the effects of radiation on specific target cells can be studied directly without the presence of extraneous factors, which complicate carcinogenesis in vivo. 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 transformation in vitro are similar to those involved in carcinogenesis in vivo, 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, 10T1/2, 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 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 vivo 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 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 transformation reflects a balance between an increase with dose in the proportion of cells that are transformed and a decrease in cell survival. This is illustrated in Figure 3-1 (Ha80). For gamma rays and other low-LET radiations, the cell survival curve is characterized by a broad initial shoulder region before it becomes steeper and approaches an exponential function of dose at higher doses (Figure 3-1) (Ha80). 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 Figure 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.

FIGURE 3-1. Probability of survival (top) and transformation per irradiated cell (bottom) as a function of dose (Ha80).


Probability of survival (top) and transformation per irradiated cell (bottom) as a function of dose (Ha80).

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 (Lu85). Using C3H10T1/2 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, Hi85). 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 effectiveness (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 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 cytotoxicity increases with increasing LET of the radiation. Hence, if the transformation frequencies for each type of high-LET particle are plotted against the corresponding 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 significant frequency of transformation at doses of high-LET radiations that have very little effect on cell survival.

Figure 3-2 (Ha87a) 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).

FIGURE 3-2. Cell survival curves and dose response relationships for oncogenic transformation for C3H10T1/2 cells irradiated with either gamma rays or high-LET helium-3 ions.


Cell survival curves and dose response relationships for oncogenic transformation for C3H10T1/2 cells irradiated with either gamma rays or high-LET helium-3 ions. Transformation frequencies are expressed in two ways; per surviving cell and per cell initially (more...)

Neutrons are also highly effective at inducing transformation. Figure 3-3 shows the variation of RBE with neutron energy over a wide range, which is similar to that received by individuals during the bombing of Hiroshima (Mi89). 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 (Hi85).

FIGURE 3-3. RBEm for cell curvinal and for oncogenic transformation as a function of neutron energy and C3H10T1/2 cells irradiated with monoenergetic neutrons (Mi89).


RBEm for cell curvinal and for oncogenic transformation as a function of neutron energy and C3H10T1/2 cells irradiated with monoenergetic neutrons (Mi89).

Alpha Particles

The transforming ability of alpha particles also has been studied extensively with in vitro transformation systems. Robertson et al. (Ro83) showed that the RBE for transformation by plutonium-238 alpha particles 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 the C3H10T1/2 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 (Hi87).

Previous studies by Lloyd et al. (Ll79) showed that at a dose corresponding 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-O-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) (Ke78). This alteration of the dose-response relationship also occurs in promotion by TPA of radiation carcinogenesis in vivo (Figure 3-5) (Fr84). While promotion can greatly enhance radiation transformation, other agents can suppress radiation transformation or the enhancement by TPA (Ke88). 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.

FIGURE 3-4. Dose-response curve for the induction of radiation transformation, with or without enhancement by TPA.


Dose-response curve for the induction of radiation transformation, with or without enhancement by TPA. Note how a promoter changes a linear quadratic response to a linear one (Ke78).

FIGURE 3-5. U.


U.V. light-induced skin cancer, with and without promotion by TPA (Fr84).

FIGURE 3-6. Suppressive effect of a protease inhibitor (antipain) on radiation transformation in vitro, both with and without promotion by TPA (Ke88).


Suppressive effect of a protease inhibitor (antipain) on radiation transformation in vitro, both with and without promotion by TPA (Ke88).

FIGURE 3-7. Effects of vitamin A analogues, selenium, vitamin E, 3-amino-benzamide, and TPA, at 4 Gy and T3 (thyroid hormone) at 3 Gy on radiation transformation (Ha87a).


Effects of vitamin A analogues, selenium, vitamin E, 3-amino-benzamide, and TPA, at 4 Gy and T3 (thyroid hormone) at 3 Gy on radiation transformation (Ha87a).

The frequency of transformation resulting from a given dose of radiation 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 hypothyroid 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 genes that are thought to be the sites of oncogenic somatic mutations. Over the past decade, research on the mechanisms of carcinogenesis has focused on such genes, of which two broad classes are now known to exist: (1) protooncogenes and (2)tumor-suppressor genes, or antioncogenes (Kn85).


Protooncogenes, which may give rise to oncogenes, seem to be important in the origin of at least some forms of human cancer. The list of such genes has grown apace with new means for identifying them. Alterations of the ras protooncogene have now been observed in several different types of radiation-induced tumors, including murine lymphomas (Gu84a, b), plutonium-induced malignancies (Fr86b), and radiation-induced rat skin tumors (Sa87, Ga88, Ga86). Radiation has also been shown to activate other oncogenes presumed to be involved in carcinogenesis, including c-myc (Sa87, Ga86, Ga88) and oncogenes that are not members of the ras gene family but which cause transformation in the NIH 3T3 cell transfection assay system (Bo87, Ja88). The activation of myc has been shown to occur by amplification, translocation, and internal rearrangements.

Although there is evidence for some specificity in the pattern of oncogene alterations that is produced by a given carcinogen, it is still not possible on the basis of an oncogene ''signature" to determine the cause of a given tumor, that is, whether the tumor was caused by radiation or some other carcinogen.

The stage at which a given oncogene is activated in the carcinogenic process also remains to be determined. While in some instances activation may occur as a late step in carcinogenesis (Su83, Su84, Ru84), evidence implies that in other instances it may occur early (Ba87, Ba87b). It is note-worthy that protooncogene loci are involved in the specific chromosomal changes that are associated with certain types of cancer (Ha87a, Ro84). This implies that such alterations of protooncogene structure or function play a causal role in the occurrence of those types of cancer. It is not known, however, whether the changes are early or late events in the origin of the neoplasms (Li80a, Fi81).

Some oncogene alterations clearly represent steps in tumor progression. An example is the amplification of the myc family of oncogenes in neuroblastomas and in small-cell carcinomas of the lung (Br84, Na86). This amplification is often cytogenetically evident in the form of double minute chromosomes consisting of repeated chromosomal pieces, including the oncogene in question. In these instances amplification signifies an advanced stage of disease and carries a poor prognosis.

A role for oncogenes in the earliest stage of oncogenic transformation could be better supported if individuals who carried such mutations in their germ lines were found. This has not been found as yet in humans, but susceptible mice have been produced experimentally by transgenically introducing an activated oncogene into the germ line. Mice with a strong predisposition for the development of lymphoma or mammary cancer have resulted from the introduction of a c-myc gene, fused with an immunoglobulin enhancer, or with the strong long terminal repeat (LTR) promoter of the mammary tumor virus, respectively (Ad85, St84). The tumors are clonally distinct, however, indicating that at least one somatic event occurred subsequently in their development. This finding parallels results of in vitro experiments showing a requirement for the activation of at least two different oncogenes in the transformation of normal rat embryo cells (La83a,b).

Tumor-Suppressor Genes (Antioncogenes)

The second class of cancer genes that has been identified was discovered through studies of individuals with inherited predispositions for specific cancers. For many cancers including carcinomas of colon, breast, lung, stomach, ovary, uterus, kidney and bladder, glioma, melanoma, leukemias, and lymphomas there is a subgroup of persons at higher than normal risk by virtue of the fact that they have inherited a specific mutation. This type of predisposition is transmitted in a Mendelian dominant fashion, although the different underlying mutations vary in their penetrances. Well-known examples of such predisposing conditions are familial polyposis coli (chromosome 5, Wilms' tumor (chromosome 11), and the hereditary form of retinoblastoma (chromosome 13). The latter tumor has been the prototype in research on this group of genes (Kn85).

About 40% of the individuals with retinoblastoma carry germ-line mutations that predispose them to the disease. The offspring of such persons have a 50% risk of developing the tumor. About 30% of the individuals with retinoblastoma have bilateral disease; all of the latter carry the germ-line mutation. A small fraction of cases (3-5%) bear a constitutional deletion in chromosome 13, a finding that has facilitated the 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, Kn85). 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 recessive. 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 osteosarcoma 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 alleles 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 (St76). 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 telangiectasia, Fanconi's anemia, and Bloom's syndrome, are recessively inherited conditions that predispose the chromosomes of an individual to breakage and/or defective repair of DNA damage (Han86). 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 chromatid, and even homologous chromosome, exchanges. The molecular defect apparently involves a ligase that is important in the repair of DNA damage (Ch87, Wi87). 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, Go86). 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 carcinogenesis.

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 (He84). 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.

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, promotion, 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 (UN82). The mechanisms through which these factors influence susceptibility 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 inhaled 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 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-specific 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 occupational 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.


  • Ad85 Adams, J. M., A. W. Harris, C. A. Pinkert, L. M. Corcoran, W. S. Alexander, S. Cory, R. D. Palmiter, and R. L. Brinster. 1985. The c-myc oncogene driven by immunoglobin enhancers induces lymphoid malignancy in transgenic mice. Nature 318:533-538. [PubMed: 3906410]
  • Ar54 Armitage, P., and R. Doll. 1954. The age distribution of cancer and a multistage theory of carcinogenesis. Br. J. Cancer 8:1-2. [PMC free article: PMC2007940] [PubMed: 13172380]
  • Ay84 Ayesh, R., J. R. Idle, J. C. Ritchie, M. J. Crothers, and M. R. Hetzel. 1984. Metabolic oxidation phenotypes as markers for susceptibility to lung cancer. Nature 312:169-170. [PubMed: 6504125]
  • Ba84 Balmain, A., M. Ramsden, G. T. Bowden, and J. Smith. 1984. Activation of mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307:658-660. [PubMed: 6694757]
  • Ba87 Balmain, A., K. Brown, R. Bremner, M. Quintanilla, and M. Archer. 1987. The action of chemical carcinogens and oncogenic retroviruses in mouse skin tumor induction. Pp. 501-506 in Radiation Research Proceedings of the 8th International Congress of Radiation Research, vol. 2, Edinburgh, July 1987, E. M. Fielden, editor; , J. F. Fowler, editor; , J. H. Henry, editor; , and D. Scott, editor. , eds. Philadelphia: Taylor and Francis.
  • Ba87b Barbacid, M. 1987. ras genes. Annu. Rev. Biochem. 56:779-827. [PubMed: 3304147]
  • Be75 Berenblum, I. 1975. Sequential aspects of chemical carcinogenesis: Skin. Pp. 323-344 in Cancer: A Comprehensive Treatise, Vol. 1, F. F. Becker, editor. . New York: Plenum.
  • Bi82 Birnboim, H. C. 1982. DNA strand breakage in human leukocytes exposed to a tumor promoter, phorbol myristate acetate. Science 215:1247-1249. [PubMed: 6276978]
  • Bo14 Boveri, T. H. 1914. Zur Frage der Entstehung maligner Tumoren (On the problem of the origin of malignant tumors). Jena, German Democratic Republic: Fisher.
  • Bo74 Borek, C., and E. J. Hall. 1974. Effect of split doses of x rays on neoplastic transformation of single cells. Nature 252:499-501. [PubMed: 4431478]
  • Bo74a Boutwell, R. K. 1974. The function and mechanism of promoters of carcinogenesis. CRC Crit. Rev. Toxicol. 2:419-443. [PubMed: 4822436]
  • Bo87 Borek, C., A. Ong, and H. Mason. 1987. Distinctive transforming genes in x-ray transformed mamalian cells. Proc. Natl. Acad. Sci. USA 84:794-798. [PMC free article: PMC304302] [PubMed: 3027705]
  • Br77 Braun, A. 1977. The story of cancer: On its nature, causes and control. Reading, Mass.: Wesley.
  • Br84 Brodeur, G. M., R. C. Seeger, M. Schwab, H. E. Barmus, and J. M. Bishop. 1984. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224:1121-1124. [PubMed: 6719137]
  • Ca82 Cartwright, R. A., R. W. Glasham, H. J. Rogers, R. A. Ahmad, D. Barham-Hall, E. Higgins, and M. A. Kahn. 1982. The role of N-acetyltransferase phenotypes in bladder carcinogenesis: A pharmacogenetics epidemiological approach to bladder cancer. Lancet ii:842-846.
  • Ca83 Cavenee, W. K., T. P. Druja, R. A. Phillips, W. F. Benedict, R. Godbout, B. L. Gallie, A. L. Murphree, L. C. Strong, and R. L. White. 1983. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 205:779-784. [PubMed: 6633649]
  • Ch87 Chan, J. Y. H., F. F. Becker, J. German, and J. H. Ray. 1987. Altered DNA ligase I activity in Bloom's syndrome cells. Nature 325:357-359. [PubMed: 3808032]
  • Cl86b Clifton, K. H. 1986. Cancer risk per clonogenic cell in vivo: Speculation on the relationship of both cancer incidence and latency to target cell number. Proceedings of the 14th International Cancer Congress, Budapest.
  • Cl86a Clifton, K. H., M. A. Tanner, and M. N. Gould. 1986. Assessment of radiogenic cancer initiation frequency per clonogenic rat mammary cell in vivo. Cancer Res. 46:2390-2395. [PubMed: 3697982]
  • Co83 Copeland, E. S., editor. , ed. 1983. A National Institutes of Health Workshop Report. Free radicals in promotion—a chemical pathology study section workshop. Cancer Res. 43:5631-5637. [PubMed: 6616490]
  • Em81 Emwerit, I., and P. A. Cerutti. 1981. Tumor promoter phorbo1-12-myristate-13-acetate induces chromosomal damage via indirect action. Nature 293:144-146. [PubMed: 7266668]
  • Fa77 Fabre, F., and H. Roman. 1977. Genetic evidence for inducibility of recombination competence in yeast. Proc. Nat. Acad. Sci. USA 74:1667-1671. [PMC free article: PMC430853] [PubMed: 323860]
  • Fa80 Fahmy, M. J., and O. G. Fahmy. 1980. Intervening DNA insertions and the alteration of gene expression by carcinogens. Cancer Res. 40:3374-3382. [PubMed: 6253062]
  • Fi81 Fialkow, P. J., P. J. Martin, V. Najfeld, G. K. Penfold, R. J. Jacobson, and J. A. Hansen. 1981. Evidence for a multistep pathogenesis of chronic myelogenous leukemia. Blood 58:158-163. [PubMed: 6972238]
  • Fi85 Fisher, S. M., and L. M. Adams. 1985. Suppression of tumor-promoter induced chemiluminescence in mouse epidermal cells by several inhibitors of arachinoic acid metabolism. Cancer Res. 45:3130-3136. [PubMed: 2988761]
  • Fr84 Fry, R. J. M., and R. D. Ley. 1984. Ultraviolet radiation carcinogenesis. Pp. 73-96 in Mechanisms of Tumor Promotion, Vol. II, Tumor Promotion and Skin Carcinogenesis, T. J. Slaga, editor. , ed. Boca Raton, FL: CRC Press.
  • Fr86a Friend, S. H., R. Bernards, S. Rogelj, R. A. Weinberg, J. M. Rappaport, D. M. Albert, and T. P. Druja. 1986. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:643-646. [PubMed: 2877398]
  • Fr86b Frazier, M. E., R. A. Lindberg, D. M. Mueller, A. Gee, and T. M. Seed. 1986. Oncogene involvement in plutonium-induced carcinogenesis. Int. J. Rad. Biol. 49:542-543.
  • Fu87 Fujiki, H., and T. Sugimura. 1987. New classes of tumor promoters: Teleocidin, aplysiatoxin and palytoxin. Adv. Cancer Res. 49:223-264. [PubMed: 2890278]
  • Fu87b Fung, Y.-K. T., A. L. Murphree, A. t'Ang, J. Qian, S. H. Hinrichs, and W. F. Benedict. 1987. Structural evidence for the authenticity of the human retinoblastoma gene. Science 236:1657-1661. [PubMed: 2885916]
  • Ga86 Garte, S. J., M. J. Sawey, and F. J. Burns. 1986. Oncogenes activated in radiation-induced rat skin tumors. Pp. 389-397 in Radiation Carcinogenesis and DNA alterations, F. J. Burns, editor; , A. C. Upton, editor; , and G. Silini, editor. , eds. New York: Plenum.
  • Ga88 Garte, S. J., M. J. Sawey, F. J. Burns, M. Felber, and T. Ashkenazi-Kimmel. 1982. Multiple oncogene activation in a radiation carcinogenesis model. In Anticarcinogenesis and Radiation Protection, P. A. Cerutti, editor; , O. F. Nygaard, editor; , and M. G. Simic, editor. , eds. New York: Plenum Press.
  • Go81 Goldstein, B. O., G. Witz, M. Amoruso, D. S. Stone, and W. Troll. 1981. Morphonuclear leukocyte superoxide anion radical (O2) production by tumor promoters. Cancer Lett. 11:257-262. [PubMed: 6265062]
  • Go86 Gonzalez, F. J., A. K. Jaiswal, and D. W. Nebert. 1986. P-450 genes: Evolution, regulation, and relationship to human cancer and pharmacogenetics. Cold Spring Harbor Symp. Quant. Biol. 51:879-890. [PubMed: 3472766]
  • Gu84a Guerrero, I., P. Calzava, A. Mayer, and A. Pellicer. 1984. A molecular approach to leukemogenesis; mouse lymphomas contain an activated c-ras oncogene. Proc. Natl. Acad. Sci. 181:202-205. [PMC free article: PMC344639] [PubMed: 6582476]
  • Gu84b Guerrero, I., A. Villasante, V. Corces, and A. Pellicer. 1984. Activation of a c-K-ras oncogene by somatic mutation in mouse lymphomas induced by gamma radiation. Science 225:1159-1162. [PubMed: 6474169]
  • Hah86 Hahn, P., L. N. Kapp, W. F. Morgan, and R. B. Painter. 1986. Chromosomal changes without DNA overproduction in hydroxyurea-treated mammalian cells: Implications for gene amplification. Cancer Res. 46:4607-4612. [PubMed: 3731112]
  • Ha81 Hall, E. J., and R. C. Miller. 1981. The how and why of in vitro oncogenic transformation. Radiat. Res. 87:208-223. [PubMed: 7267991]
  • Ha85 Hall, E. J., and T. K. Hei. 1985. Oncogenic transformation in vitro by radiations of varying LET. Radiat. Protect. Dosimetry 13:149-151.
  • Ha87a Hall, E. J., and T. K. Hei. 1987. Oncogenic transformation by radiation and chemicals. In Proceedings of the VIIth International Congress of Radiation Research, E. M. Fielden, editor; , J. F. Fowler, editor; , J. H. Hendry, editor; , and D. Scott, editor. , eds. London: Taylor and Francis.
  • Ha87b Haluska, F. G., Y. Tsujimoto, and C. M. Croce. 1987. Oncogene activation by chromosome translocation in human malignancy. Annu. Rev. Genet. 21:321-345. [PubMed: 3327468]
  • Ha79 Han, A., and M. M. Elkind. 1979. Transformation of mouse C3H10T1/2 cells by single and fractionated doses of x rays and fission-spectrum neutrons. Cancer Res. 39:123-130. [PubMed: 761182]
  • Ha80 Han, A., C. K. Hill, and M. M. Elkind. 1980. Repair of cell killing and neoplastic transformation at reduced dose rates of 60Co gamma rays. Cancer Res. 40:3328-3332. [PubMed: 7427946]
  • Han86 Hanawalt, P. C., and A. Sarasin. 1986. Cancer-prone hereditary diseases with DNA processing abnormalities. Trends Genet. 2:124-129.
  • Han85 Hansen, M. F., A. Koufos, B. L. Gallie, R. A. Phillips, O. Fodstad, A. Brogger, T. Gedde-Dahl, and W. K. Cavenee. 1985. Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition. Proc. Natl. Acad. Sci. USA 82:1-5. [PMC free article: PMC391023] [PubMed: 2994066]
  • He83 Hennings, H., R. Shores, M. L. Wenk, E. F. Spangler, R. Tarone, and S. H. Yuspa. 1983. Malignant conversion of mouse skin tumors is increased by tumor initiators and unaffected by tumor promoters. Nature 304:67-69. [PubMed: 6866091]
  • He84 Hecht, F., and G. R. Sutherland. 1984. Fragile sites and cancer breakpoints. Cancer Genet. Cytogenet. 12:179-181. [PubMed: 6722758]
  • He88 Hei, T. K., E. J. Hall, and M. Zaider. 1988. Oncogenic transformation by charged particles of defined LET. Carcinogenesis. [PubMed: 3365835]
  • Hi87 Hieber, L., G. Ponsel, H. Roos, S. Senn, E. Fromke, and A. N. Kellerer. 1987. Absence of dose-rate effect in the transformation of C3H10 1/2 cells by alpha particles. Int. J. Rad. Biol. 52:859-869. [PubMed: 3500927]
  • Hi84 Hill, C. K., A. Han, F. Buonaguro, and M. M. Elkind. 1984. Multifractionation of 60Co gamma-rays reduces neoplastic transformation in vitro . Carcinogenesis 5:193-197. [PubMed: 6697436]
  • Hi85 Hill, C. K., B. A. Carnes, A. Han, and M. M. Elkind. 1985. Neoplastic transformation is enhanced by multiple low doses of fission spectrum neutrons. Radiat. Res. 101:404-410. [PubMed: 4070554]
  • Ja86 Jaffe, D. R., and G. T. Bowden. 1986. Ionizing radiation as an initiator in the mouse two-stage model of skin tumor formation. Radiat. Res. 106:156-165. [PubMed: 3704109]
  • Ja87 Jaffe, D. R., J. F. Williamson, G. T. Bowden. 1987. Ionizing radiation enhances malignant progression of mouse skin tumors. Carcinogenesis 8:1753-1755. [PubMed: 3664970]
  • Ja88 Jaffe, D. R., and G. T. Bowden. 1988. Enhanced malignant progression of mouse skin tumors by ionizing radiation and activation of oncogenes in radiation induced tumors. In Radiation Research: Proceedings of the 8th International Congress of Radiation Research, Vol. 1, Edinburgh, July 1987, E. M. Fielden, editor; , J. F. Fowler, editor; , J. H. Henry, editor; , and D. Scott, editor. , eds. Philadelphia: Taylor and Francis.
  • Ke78 Kennedy, A. R., S. Mondal, C. Heidelberger, and J. B. Little. 1978. Enhancement of x ray transformation by 12-O-tetradecanoyl phorbol 13 acetate in a cloned line C3H mouse embryo cells. Cancer Res. 38:439-443. [PubMed: 620412]
  • Ke84a Kennedy, A. R. 1984. Promotion and other interactions between agents in the induction of transformation in vitro in fibroblasts. Pp. 13-55 in Mechanisms of Tumor Promotion, Vol. III, Tumor Promotion and Carcinogenesis in Vitro, T. J. Slaga, editor. , ed. Boca Raton, Fla.: CRC Press.
  • Ke84b Kennedy, A. R., and J. B. Little. 1984. Evidence that a second event in x-ray induced oncogenic transformation in vitro occurs during cellular proliferation. Rad. Res. 99:228-248. [PubMed: 6463204]
  • Ke85a Kennedy, A. R. 1985. Evidence that the first step leading to carcinogen-induced malignant transformation is a high frequency, common event. Pp. 455-364 in Carcinogenesis: A Comprehensive Survey, Vol. 9, Mammalian Cell Transformation: Mechanisms of Carcinogenesis and Assays for Carcinogens, J. C. Barrett, editor; and R. W. Tennant, editor. , eds. New York: Raven. [PubMed: 4053082]
  • Ke85b Kennedy, A. R. 1985. The conditions for the modification of radiation transformation in vitro by a tumor promoter and protease inhibitors. Carcinogenesis 6:1441-1446. [PubMed: 4042273]
  • Ke86 Kennedy, A. R. 1986. Role of free radicals in the initiation and promotion of radiation-induced and chemical carcinogen induced cell transformation. Pp. 201-209 in Oxygen and Sulfur Radicals in Chemistry and Medicine, A. Breccia,, editor; M. A. J. Rodgers, editor; , and G. Semerano, editor. , eds. Bologna, Italy: Edizioni Scientifiche, Lo Scarabeo.
  • Ke88 Kennedy, A. R., and P. C. Billings. 1988. Anticarcinogenic actions of protease inhibitors. In Proceedings of the 2nd International Conference on Anticarcinogenesis and Radiation Protection, P. Cerutti, editor; , O. F. Nygaard, editor; , and M. Simic, editor. , eds. New York: Plenum.
  • Ki78 Kinsella, A., and M. Radman. 1978. Tumor promoter induces sister chromatid exchanges: Relevance to mechanisms of carcinogenesis. Proc. Natl. Acad. Sci. USA 75:6149-6153. [PMC free article: PMC393136] [PubMed: 282631]
  • Kn85 Knudson, A. G. 1985. Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 45:1437-1443. [PubMed: 2983882]
  • Ko82 Kouri, R. E., C. E. McKinney, D. J. Slomiany, D. R. Snodgrass, N. P. Wray, and T. L. McLemore. 1982. Positive correlation between high aryl hydrocarbon hydroxylase activity and primary lung cancer as analyzed in cryopreserved lymphocytes. Cancer Res. 42:5030-5037. [PubMed: 6291746]
  • La83a Land, H., L. F. Parada, and R. A. Weinberg. 1983. Cellular oncogenes and multistep carcinogenesis. Science 222:771-778. [PubMed: 6356358]
  • La83b Land, H., L. F. Parada, and R. A. Weinberg. 1983. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304:596-602. [PubMed: 6308472]
  • Le84 LeBeau, M. M., and J. D. Rowley. 1984. Heritable fragile sites in cancer. Nature 308:607-608. [PubMed: 6709072]
  • Le87a Lee, W. H., R. Bookstein, F. Hong, L. J. Young, J. Y. Shew, and E. Y.-H. P. Lee. 1987. Human retinoblastoma susceptibility gene: Cloning, identification, and sequence. Science 235:1394-1399. [PubMed: 3823889]
  • Le87b Lee, W. H., J. Y. Shew, F. D. Hong, T. W. Sery, L. A. Donoso, L. J. Young, R. Bookstein, and E. Y.-H. P. Lee. 1987. The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity. Nature 329:642-645. [PubMed: 3657987]
  • Li77 Little, J. B., and J. R. Williams. 1977. Effects of ionizing radiation on mammalian cells. Pp. 127-155 in Handbook of Physiology, S. R. Geiger, editor; , H. L. Falk, editor; , S. D. Murphy, editor; , and P. H, editor; . K. Lee, editor. , eds. Bethesda, Md.: American Physiological Society.
  • Li78 Little, J. B., R. B. McGandy, and A. R. Kennedy. 1978. Interactions between polonium 210alpha radiation, benzo(a)pyrene, and 0.9% NaCl solutions instillations in the induction of experimental lung cancer. Cancer Res. 38:1929-1935. [PubMed: 657130]
  • Li79 Little, J. B. 1979. Quantitative studies of radiation transformation with the A31-11 mouse Balb/3T3 cell line. Cancer Res. 39:1474-1480. [PubMed: 427792]
  • Li80a Lisker, R., L. Casas, O. Mutchinick, F. Perez-Chavez, and J. Labardini. 1980. Late-appearing Philadelphia chromosome in two patients with chronic myelogenous leukemia. Blood 56:812-814. [PubMed: 6932978]
  • Li80b Little, J. W., S. H. Edmiston, L. Z. Pacelli, and D. W. Mount. 1980. Cleavage of the Escherichia coli lex A protein by the rec A portease. Proc. Natl. Acad. Sci. USA 77:3225-3229. [PMC free article: PMC349587] [PubMed: 6447873]
  • Ll79 Lloyd, E. L., M. A. Gemmell, C. B. Henning, D. S. Gemmell, and B. J. Zabransky. 1979. Transformation of mammalian cells by alpha particles. Int. J. Radiat. Biol. 36:467-478. [PubMed: 317497]
  • Lo44 Lorenz, E. 1944. Radioactivity and lung cancer: A critical review of lung cancer in the mines of Schneeberg and Joachimstal. J. Natl. Cancer Inst. 5:1-15.
  • Lu71 Lundin, F. E., J. K. Wagoner, Jr., and V. E. Archer. 1971. Radon daughter exposure and respiratory cancer: Quantitative and temporal aspects. NIOSH-NIEHS Joint Monograph No. 1. Washington, D.C.: U.S. Public Health Service.
  • Lu85 Lurie, A. G., and A. R. Kennedy. 1985. Single, split, and fractionated dose x-irradiation-induced malignant transformation in A31-11 mouse Balb-3T3 cells. Cancer Lett. 29:169-176. [PubMed: 4075285]
  • Ma76 Maruyama, K., R. Natori, and Y. Nonomura. 1976. Down's syndrome and related abnormalities in an area of high background radiation in coastal Kerala. Nature 262:60-61. [PubMed: 132614]
  • Ma83 Marx, J. H. 1983. Do tumor promoters affect DNA after all? Science 219:158-159. [PubMed: 6849126]
  • Me77 Meyn, M. S., T. Rossman, and W. Troll. 1983. A protease inhibitor blocks SOS functions in Escherichia coli; antipain prevents repressor in-activiation, ultraviolet mutagenesis and filamentous growth. Proc. Natl. Acad. Sci. USA 74:1152-1156. [PMC free article: PMC430629] [PubMed: 322145]
  • Mi89 Miller, R. C., D. J. Brenner, C. R. Geard, K. Komatsu, S. A. Marino, and E. J. Hall. Neutron-Energy-Dependent Oncogenic Transformation of C3H/10T1/2 Mouse Cells. Radiat. Res. 117:114-127. [PubMed: 2913605]
  • Mo64 Mole, R. H. 1964. Cancer production by chronic exposure to penetrating gamma irradiation. Natl. Cancer Inst. Monogr. 14:217-290. [PubMed: 14147137]
  • Mo81 Moolgavkar, S. H., and A. G. Knudson. 1981. Mutation and cancer: A model for human carcinogenesis. J. Natl. Cancer Inst. 66:1037-1052. [PubMed: 6941039]
  • Na79 Nagasawa, H., and J. Little. 1979. Effect of tumor promoters, protease inhibitors, and repair processes on X ray-induced sister chromatid exchanges in mouse cells. Proc. Natl. Acad. Sci. USA 76:1943-1947. [PMC free article: PMC383509] [PubMed: 287035]
  • Na86 Nau, M. M., B. J. Brooks, D. N. Carney, A. F. Gazdar, J. F. Battey, E. A. Sausville, and J. D. Minna. 1986. Human small-cell lung cancers show amplification and expression of the N-myc gene. Proc. Natl. Acad. Sci. USA 83:1092-1096. [PMC free article: PMC323017] [PubMed: 2869482]
  • NRC88 National Academy of Sciences, National Research Council. Committee on the Biological Effects of Ionizing Radiations (BEIR IV). 1988. Health Risks of Radon and Other Internally Deposited Alpha Emitters. Washington, D.C.: National Academy Press. [PubMed: 25032289]
  • Pa81 Parry, J. M., E. M. Parry, and J. C. Barrett. 1981. Tumor promoters induce mitotic aneuploidy in yeast. Nature 294:263-265. [PubMed: 7029309]
  • Pe85 Pelling, J. C., and T. J. Slaga. 1985. Cellular mechanisms for tumor promotion and enhancement. Pp. 369-393 in Carcinogenesis, Vol. 8, M. J. Mass, editor. et al., ed. New York: Raven. [PubMed: 2985260]
  • Ro83 Robertson, J. B., A. Koehler, J. George, and J. B. Little. 1983. Oncogenic transformation of mouse Balb/3T3 cells by plutonium-238 alpha particles. Radiat. Res. 96:261-274. [PubMed: 6647760]
  • Ro84 Rowley, J. B. 1984. Biological implications of consistent chromosome rearrangements in leukemia and lymphoma. Cancer Res. 44:3159-3168. [PubMed: 6378364]
  • Ru84 Rubin, H. 1984. Mutations and oncogenes—cause or effect. Nature 309:518. [PubMed: 6728009]
  • Ry71 Ryser, H. J. P. 1971. Chemical carcinogenesis. N. Engl. J. Med. 285:721-734. [PubMed: 4942982]
  • Sa84 Samet, J. M., D. M. Kutvirt, R. J. Waxweiler, and C. R. Key. 1984. Uranium mining and lung cancer in Navajo men. N. Engl. J. Med. 310:1581-1484. [PubMed: 6717538]
  • Sa87 Sawey, M. J., A. T. Hood, F. J. Burns, and S. J. Garte. 1987. Activation of myc and ras oncogenes in primary rat tumors induced by ionizing radiation. Mol. Cell. Biol. 7:932-935. [PMC free article: PMC365153] [PubMed: 3547086]
  • Sc85 Scott, R. E., and P. B. Maercklein. 1985. An initiator of carcinogenesis selectively and stably inhibits stem cell differentiation: A concept that initiation of carcinogenesis involves multiple phases. Proc. Natl. Acad. Sci. 82:2995-2999. [PMC free article: PMC397693] [PubMed: 3857629]
  • Sh82 Shami, S., L. Thibideau, A. R. Kennedy, and J. B. Little. 1982. Proliferative and morphological changes in the pulmonary epithelium of the Syrian golden hamster lung during carcinogenesis initiated by 210Po alpha radiation. Cancer Res. 42:1405-1411. [PubMed: 7060014]
  • Sl83 Slaga, T. J., V. Solanki, and M. Logani. 1983. Studies on the mechanism of action of antitumor promoting agents: suggestive evidence for the involvement of free radicals in promotion. Pp. 471-485 in Radioprotectors and Anticarcinogens, O. F. Nygaard, editor; and M. G. Simic, editor. , eds. New York: Academic Press.
  • Sl83 Slaga, T. J., editor. , ed. 1980. Carcinogenesis: A Comprehensive Survey, Vol. 5. Modifiers of Chemical Carcinogenesis. New York: Raven Press.
  • Sp85 Sporn, M. B., and A. B. Roberts. 1985. Autocrine growth factors and cancer. Nature 313:745-747. [PubMed: 3883191]
  • St76 Stanbridge, E. J. 1976. Suppression of malignancy in human cells. Nature 260:17-20. [PubMed: 1264187]
  • Ste84 Stewart, T., P. K. Pattengale, and P. Leder. 1984. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 38:627-637. [PubMed: 6488314]
  • Su73 Suss, R., V. Kinzel, and J. D. Scribner. 1984. Cancer-experiments and concepts. New York: Springer-Verlag.
  • Su83 Sukumar, S., V. Notario, D. Martin-Zanca, and M. R. Barbacid. 1983. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-l locus by single point mutations. Nature 306:658-551. [PubMed: 6318112]
  • Su84 Sukumar, S., S. Pulciani, J. Doniger, J. A. DiPaolo, C. Evans, B. Zbar, and M. Barbacid. 1984. Science 223:1197-1199. [PubMed: 6322298]
  • Tr82 Trosko, J. E., L. P. Yotti, S. T. Warren, G. Tsushimoto, and C. C. Chang. Inhibition of cell-cell communication by tumor promoters. 1982. Pp. 565-585 in Carcinogenesis, Vol. 7, E. Hecker, editor. et al., eds. [PubMed: 7039834]
  • UN82 United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). 1982. Ionizing Radiation: Sources and Biological Effects. Report A/37/45. Thirty Seventh Session, Supplement No. 45. New York: United Nations.
  • Wa85 Wattenberg, L. W. 1985. Chemoprevention of cancer. Cancer Res. 45:1-8. [PubMed: 3880665]
  • Wa88 Watanabe, H., M. A. Tanner, F. E. Domann, M. N. Gould, and K. H. Clifton. In press. Inhibition of carcinoma formation and of vascular invasion in grafts of radiation-initiated thyroid clonogens by unirradiated thyroid cells. Carcinogenesis. [PubMed: 3402028]
  • We87 Weinberg, C. R., K. G. Brown, and D. G. Hoel. 1987. Altitude radiation, and mortality from cancer and heart disease. Radiat. Res. 112:381-390. [PubMed: 3685264]
  • Wi76 Witkin, E. M. 1976. Ultraviolet mutagenesis and inducible DNA repair in escherichia coli. Bacteriol. Rev. 40:869-907. [PMC free article: PMC413988] [PubMed: 795416]
  • Wi84 Wintersberger, U. 1984. The selective advantage of cancer cells; a consequence of genome mobilization in the course of the induction of DNA repair processes? (Model studies of yeast). Pp. 311-323 in Advances in Enzyme Regulation, Vol. 22, G. Weber, editor. ed. New York: Pergamon. [PubMed: 6382954]
  • Wi87 Willis, A. E., and T. Lindahl. 1987. DNA ligase I deficiency in Bloom's syndrome. Nature 325:355-357. [PubMed: 3808031]
  • Ya85 Yang, T. C. H., L. M. Craise, M. T. Mei, and C. A. Tobias. 1985. Neoplastic cell transformation by heavy charged particles. Radiat. Res. 104: S177-S178.
Copyright © 1990 by the National Academy of Sciences.
Bookshelf ID: NBK218707


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