Radioimmunotherapy: Clinical results and dosimetric considerations

Radiolabeled antibodies for cancer therapy are being investigated in clinical trials in more than 30 centers. ¹³¹Iodine-labeled antibody (Ab) therapy of solid tumors has produced few responses when given alone. When given in conjunction with chemotherapy and external beam therapy in hepatoma patients, objective responses have occurred. Because of the short range of ¹³¹I, ⁹⁰Y and ¹⁸⁶Re are being studied and objective responses have occurred in patients without the addition of other therapies. ¹³¹I-labeled Ab therapy of lymphoma, a radioresponsive tumor, has produced a much higher objective response rate than in other solid tumors. Regional RIT has not been shown to offer a definite advantage over the intravenous route. Tumor doses have generally been less than 2000 cGy per treatment with some tumors receiving higher doses. The bone marrow is the dose-limiting organ for RIT and marrow cryopreservation with subsequent reinfusion may prove useful.     

Anti-CD45 Radioimmunotherapy with 90Y but Not 177Lu Is Effective Treatment in a Syngeneic Murine Leukemia Model

Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with ¹³¹I or ⁹⁰Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing ⁹⁰Y and ¹⁷⁷Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both ⁹⁰Y- and ¹⁷⁷Lu-anti-murine CD45 Ab conjugates (DOTA-30F11) targeted hematologic tissues, as at 24 hours 48.8±21.2 and 156±14.6% injected dose per gram of tissue (% ID/g) of ⁹⁰Y-DOTA-30F11 and 54.2±9.5 and 199±11.7% ID/g of ¹⁷⁷Lu-DOTA-30F11 accumulated in bone marrow (BM) and spleen, respectively. However, ⁹⁰Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 µCi ⁹⁰Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 µCi ⁹⁰Y-DOTA-30F11 had a median survival 66 days. ⁹⁰Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, ¹⁷⁷Lu- anti-CD45 RIT yielded no long-term survivors. Thus, ⁹⁰Y was more effective than ¹⁷⁷Lu for anti-CD45 RIT of AML in this murine leukemia model.     

Etiology of Leukemia—A Review

A variety of factors probably are etiologically involved in leukemia, not only in different cases but also within individual cases.Abnormalities of chromosomes have been found in various types of leukemia. Whether these chromosomal alterations are primary or secondary is undetermined, but it is likely that they are at least contributory in the development of leukemia. There is an increasing body of evidence incriminating viruses in leukemogenesis in man, and they may be a factor in all cases. Certain chemicals may be important etiologic factors in a few cases. Many different studies have established that ionizing radiation in large doses may be leukemogenic. Whether small doses of irradiation are dangerous has not been demonstrated.     

Cancer mortality risk among workers at the Mayak nuclear complex

At present, direct data on risk from protracted or fractionated radiation exposure at low dose rates have been limited largely to studies of populations exposed to low cumulative doses with resulting low statistical power. We evaluated the cancer risks associated with protracted exposure to external whole-body gamma radiation at high cumulative doses (the average dose is 0.8 Gy and the highest doses exceed 10 Gy) in Russian nuclear workers. Cancer deaths in a cohort of about 21,500 nuclear workers who began working at the Mayak complex between 1948 and 1972 were ascertained from death certificates and autopsy reports with follow-up through December 1997. Excess relative risk models were used to estimate solid cancer and leukemia risks associated with external gamma-radiation dose with adjustment for effects of plutonium exposures. Both solid cancer and leukemia death rates increased significantly with increasing gamma-ray dose (P < 0.001). Under a linear dose-response model, the excess relative risk for lung, liver and skeletal cancers as a group (668 deaths) adjusted for plutonium exposure is 0.30 per gray (P < 0.001) and 0.08 per gray (P < 0.001) for all other solid cancers (1062 deaths). The solid cancer dose-response functions appear to be nonlinear, with the excess risk estimates at doses of less than 3 Gy being about twice those predicted by the linear model. Plutonium exposure was associated with increased risks both for lung, liver and skeletal cancers (the sites of primary plutonium deposition) and for other solid cancers as a group. A significant dose response, with no indication of plutonium exposure effects, was found for leukemia. Excess risks for leukemia exhibited a significant dependence on the time since the dose was received. For doses received within 3 to 5 years of death the excess relative risk per gray was estimated to be about 7 (P < 0.001), but this risk was only 0.45 (P = 0.02) for doses received 5 to 45 years prior to death. External gamma-ray exposures significantly increased risks of both solid cancers and leukemia in this large cohort of men and women with occupational radiation exposures. Risks at doses of less than 1 Gy may be slightly lower than those seen for doses arising from acute exposures in the atomic bomb survivors. As dose estimates for the Mayak workers are improved, it should be possible to obtain more precise estimates of solid cancer and leukemia risks from protracted external radiation exposure in this cohort.     

Ionizing radiation and risk of chronic lymphocytic leukemia in the 15-country study of nuclear industry workers

In contrast to other types of leukemia, chronic lymphocytic leukemia (CLL) has long been regarded as non-radiogenic, i.e. not caused by ionizing radiation. However, the justification for this view has been challenged. We therefore report on the relationship between CLL mortality and external ionizing radiation dose within the 15-country nuclear workers cohort study. The analyses included, in seven countries with CLL deaths, a total of 295,963 workers with more than 4.5 million person-years of follow-up and an average cumulative bone marrow dose of 15 mSv; there were 65 CLL deaths in this cohort. The relative risk (RR) at an occupational dose of 100 mSv compared to 0 mSv was 0.84 (95% CI 0.39, 1.48) under the assumption of a 10-year exposure lag. Analyses of longer lag periods showed little variation in the RR, but they included very small numbers of cases with relatively high doses. In conclusion, the largest nuclear workers cohort study to date finds little evidence for an association between low doses of external ionizing radiation and CLL mortality. This study had little power due to low doses, short follow-up periods, and uncertainties in CLL ascertainment from death certificates; an extended follow-up of the cohorts is merited and would ideally include incident cancer cases.     

Historical review of occupational exposures and cancer risks in medical radiation workers

Epidemiological studies of medical radiation workers have found excess risks of leukemia, skin and female breast cancer in those employed before 1950 but little consistent evidence of cancer risk increases subsequently. Occupational radiation-related dose-response data and recent and lifetime cancer risk data are limited for radiologists and radiologic technologists and lacking for physicians and technologists performing fluoroscopically guided procedures. Survey data demonstrate that occupational doses to radiologists and radiologic technologists have declined over time. Eighty mostly small studies of cardiologists and fewer studies of other physicians reveal that effective doses to physicians per interventional procedure vary by more than an order of magnitude. For medical radiation workers, there is an urgent need to expand the limited information on average annual, time-trend and organ doses from occupational radiation exposures and to assess lifetime cancer risks of these workers. For physicians and technologists performing interventional procedures, more information about occupational doses should be collected and long-term follow-up studies of cancer and other serious disease risks should be initiated. Such studies will help optimize standardized protocols for radiologic procedures, determine whether current radiation protection measures for medical radiation workers are adequate, provide guidance on cancer screening needs, and yield valuable insights on cancer risks associated with chronic radiation exposure.     

Risk estimates for radiation-induced cancer – the epidemiological evidence

The risk of low-dose radiation exposures has – for a variety of reasons – been highly politicised. This has led to a frequently exaggerated perception of the potential health effects, and to lasting public controversies. A balanced view requires a critical reassessment of the epidemiological basis of current assumptions. There is reliable quantitative information available on the increase of cancer rates due to moderate and high doses. This provides a firm basis for the derivation of probabilities of causation, e.g. after high radiation exposures. For small doses or dose rates, the situation is entirely different: potential increases of cancer rates remain hidden below the statistical fluctuations of normal rates, and the molecular mechanisms of cancerogenesis are not sufficiently well known to allow numerical predictions. Risk coefficients for radiation protection must, therefore, be based on the uncertain extrapolation of observations obtained at moderate or high doses. While extrapolation is arbitrary, it is, nevertheless, used and mostly with the conservative assumption of a linear dose dependence with no threshold (LNT model). All risk estimates are based on this hypothesis. They are, thus, virtual guidelines, rather than firm numbers. The observations on the A-bomb survivors are still the major source of information on the health effects of comparatively small radiation doses. A fairly direct inspection of the data shows that the solid cancer mortality data of the A-bomb survivors are equally consistent with linearity in dose and with reduced effectiveness at low doses. In the leukemia data a reduction is strongly indicated. With one notable exception – leukemia after prenatal exposure – these observations are in line with a multitude of observations in groups of persons exposed for medical reasons. The low-dose effects of densely ionizing radiations – such as alpha-particles from radon decay products or high-energy neutrons – are a separate important issue. For neutrons, there is little epidemiological information. This has facilitated exaggerated claims of high neutron effects with reference to alleged dangers from transports of reactor fuel. However, in spite of limited information, it can be shown that the data from Hiroshima exclude the stated claims. New dosimetric information on neutrons may turn out to be highly informative with regard to an upper limit for the potential effects of neutrons and equally with regard to a reassessment – and a possible reduction – of risk estimates for gamma-rays. Received: 13 November 1999 / Accepted in revised form: 13 December 1999     

La radio-immunothérapie

Radioimmunotherapy (RIT) is a new modality of targeted therapy in which irradiation from radionuclides is delivered to tumor targets using monoclonal antibodies (MAb) directed to tumor-associated antigen. RIT has been developed for more than 20 years. Today, RIT can be used in clinical practice using non-ablative activity of murine anti-CD20 ⁹⁰Y-ibritumomab tiuxetan (ZevalinÒ) for treatment of patients with relapsed or refractory FL, with overall response rate of 70 to 80% and 20 to 30% of complete response. Different approaches are explored to improve efficacy of RIT in NHL: myeloablative RIT or HD treatment, RIT as consolidation after chemotherapy to target MRD, RIT in first-line treatment, fractionated RIT, RIT using other Ag targets. For solid tumors, interesting results have been obtained using anti-CEA RIT delivered as consolidation treatment or using pretargeting system.     

Combined radioimmunotherapy and chemotherapy of breast tumors with Y-90-labeled anti-Her2 and anti-CEA antibodies with taxol

Because breast cancer cells often express either Her2/neu or carcinoembryonic antigen (CEA) or both, these tumor markers are good targets for radioimmunotherapy using Y-90-labeled antibodies. We performed studies on nude mice bearing xenografts from MCF7, a cell line that has low Her2 and CEA expression, to more accurately reflect the more usual situation in breast cancer. Although uptake of In-111 anti-CEA into tumors was lower than that for In-111-labeled anti-Her2, radioimmunotherapy (RIT) with Y-90 anti-CEA was equivalent to that of Y-90 anti-Her2. When either Y-90 antibody was combined with a split-dose treatment with Taxol, the antitumor effect was greater than with either agent alone. When Y-90 anti-CEA was combined with a single dose of Taxol, the results were equivalent to the split-dose regimen. RIT plus cold Herceptin had no additional effects on tumor size reduction over RIT alone. When animals were first treated with Y-90 anti-Her2 and imaged 1-2 weeks later with In-111 anti-CEA or anti-Her2, tumor uptake was higher for anti-CEA and improved over tumor uptake with no prior RIT. These results suggest that a split dose of RIT with anti-Her2 antibody followed by anti-CEA antibody would be more effective than a single dose of either. This prediction was partially confirmed in a controlled study comparing single- vs split-dose anti-Her2 RIT followed by either anti-Her2 or anti-CEA RIT. These studies suggest that combined RIT and Taxol therapy are suitable in breast cancers expressing either low amounts of Her2 or CEA, thus expanding the number of eligible patients for combined therapies. They further suggest that split-dose RIT using different combinations of Y-90-labeled antibodies is effective in antitumor therapy.     

A two-mutation model of radiation-induced acute myeloid leukemia using historical mouse data

From studies of the atomic bomb survivors, it is well known that ionizing radiation causes several forms of leukemia. However, since the specific mechanism behind this process remains largely unknown, it is difficult to extrapolate carcinogenic effects at acute high-dose exposures to risk estimates for the chronic low-dose exposures that are important for radiation protection purposes. Recently, it has become clear that the induction of acute myeloid leukemia (AML) in CBA/H mice takes place through two key steps, both involving the Sfpi1 gene. A similar mechanism may play a role in human radiation-induced AML. In the present paper, a two-mutation carcinogenesis model is applied to model AML in several data sets of X-ray- and neutron-exposed CBA/H mice. The models obtained provide good fits to the data. A comparison between the predictions for neutron-induced and X-ray-induced AML yields an RBE for neutrons of approximately 3. The model used is considered to be a first step toward a model for human radiation-induced AML, which could be used to estimate risks of exposure to low doses.     

Inhibition of repair of DNA single strand breaks in mouse leukemia cells by actinomycin D

The effects of Actinomycin D, cytosine arabinoside and temperature shifts on the repair of single strand breaks produced in murine leukemia cell DNA by ionizing radiation have been studied. A recently introduced modification of the alkaline sucrose sedimentation methods was used, allowing breaks to be demonstrated following clinical range irradiation doses. The results contrast to previous data using standard gradient procedures and indicate that low concentrations of Actinomycin D can inhibit single strand break repair, while cytosine arabinoside is ineffective. Inhibition can also be demonstrated by temperature shifts to 3° but not 24°, paralleling previous results from cellular repair studies (Elkind-Sutton repair). The results are consistent with the hypothesis that the accumulation of sublethal radiation damage in mammalian cells may be based on residual non-repaired single strand breaks.     

A nested case-control study of leukemia mortality and ionizing radiation at the Portsmouth Naval Shipyard

A nested case-control study using conditional logistic regression was conducted to evaluate the exposure-response relationship between external ionizing radiation exposure and leukemia mortality among civilian workers at the Portsmouth Naval Shipyard (PNS), Kittery, Maine. The PNS civilian workers received occupational radiation exposure while performing construction, overhaul, repair and refueling activities on nuclear-powered submarines. The study age-matched 115 leukemia deaths with 460 controls selected from a cohort of 37,853 civilian workers employed at PNS between 1952 and 1992. In addition to radiation doses received in the workplace, a secondary analysis incorporating doses from work-related medical X rays and other occupational radiation exposures was conducted. A significant positive association was found between leukemia mortality and external radiation exposure, adjusting for gender, radiation worker status, and solvent exposure duration (OR = 1.08 at 10 mSv of exposure; 95% CI = 1.01, 1.16). Solvent exposure (including benzene and carbon tetrachloride) was also significantly associated with leukemia mortality adjusting for radiation dose, radiation worker status, and gender. Incorporating doses from work-related medical X rays did not change the estimated leukemia risk per unit of dose.     

Melanoma and ionizing radiation: is there a causal relationship?

This review was initiated in response to concerns that ionizing radiation could be a cause of melanoma. Studies presenting the relative risks for melanoma after external ionizing radiation exposure were in seven categories: (1) The Canadian Radiation Dose Registry, (2) nuclear industry workers, (3) subjects near nuclear test blasts, (4) survivors of the atomic bombings of Japan, (5) airline pilots and cabin attendants, (6) recipients of medical radiation, and (7) radiological technicians. Relative risks for leukemia in each of the studies were used to confirm the likelihood of exposure to ionizing radiation. When studies within a category were compatible, meta-analytic methods were used to obtain combined estimates of the relative risk, and a meta-regression analysis of melanoma relative risk compared to leukemia relative risk was used to examine consistency across exposure categories. Generally, exposure categories with elevated relative risks of leukemia had proportionately elevated relative risks of melanoma. This suggests that people exposed to ionizing radiation may be at increased risk of developing melanoma, although alternative explanations are possible. Future epidemiological studies of ionizing radiation effects should include melanoma as an outcome of interest.     

Analysis of mortality among Canadian nuclear power industry workers after chronic low-dose exposure to ionizing radiation

Studies of radiation-associated risks among workers chronically exposed to low doses of radiation are important, both to estimate risks directly and to assess the adequacy of extrapolations of risk estimates from high-dose studies. This paper presents results based on a cohort of 45,468 nuclear power industry workers from the Canadian National Dose Registry monitored for more than 1 year for chronic low-dose whole-body ionizing radiation exposures sometime between 1957 and 1994 (mean duration of monitoring = 7.4 years, mean cumulative equivalent dose = 13.5 mSv). The excess relative risks for leukemia [excluding chronic lymphocytic leukemia (CLL)] and for all solid cancers were 52.5 [95% confidence interval (CI): 0.205, 291] and 2.80 (95% CI: -0.038, 7.13) per sievert, respectively, both associations having P values close to 0.05. Relative risks by dose categories increased monotonically for leukemia excluding CLL but were less consistent for all solid cancers combined. Although the point estimates are higher than those found in other studies of whole-body irradiation, the difference could well be due to chance. Further follow-up of this cohort or the combination of results from multiple worker studies will produce more stable estimates and thus complement the risk estimates from higher-dose studies.     

Neutron RBEs for mouse skin at low doses per fraction

The effect of low doses of 240 kVp X rays or of 3 MeV neutrons has been investigated using skin reactions on mouse feet as the biological system. Eight or nine repeated small doses of radiation were used, followed by graded "top-up" doses to bring the reactions into a detectable range. By comparing dose-response curves, the RBE has been determined for neutron doses per fraction ranging from 0.25-1.0 Gy. The data are consistent with a limiting RBE of between 7 and 10 at very low doses. A review of other published RBE values for low doses per fraction shows a wide range of RBEs . Very few studies show a plateau value for the RBE. These findings are more consistent with dose-response data that fit a linear-quadratic model than with a multitarget single-hit model.     

A hypothesis: radiation-related leukemia is mainly attributable to the small number of people who carry pre-existing clonally expanded preleukemic cells

Human leukemia frequently involves recurrent translocations. Since radiation is a well-known inducer of both leukemia and chromosomal translocations, it has long been suspected that radiation might cause leukemia by inducing specific translocations. However, recent studies clearly indicate that spontaneous translocations specific to acute lymphocytic leukemia (ALL) actually occur much more frequently than do leukemia cases with the same translocations. Moreover, the ALL-associated translocation-bearing cells are often found to have clonally expanded in individuals who do not develop ALL. Since radiation-induced DNA damage is generated essentially randomly in the genome, it does not seem likely that radiation could ever be responsible for the induction of identical translocations of relevance to ALL in multiple cells of an individual and hence be the primary cause of radiation-related leukemia. An alternative hypothesis described here is that the radiation-related ALL risk for a population is almost entirely attributable to a small number of predisposed individuals in whom relatively large numbers of translocation-carrying pre-ALL cells have accumulated. This preleukemic clone hypothesis explains various known characteristics of radiation-related ALL and implies that people who do not have substantial numbers of preleukemic cells (i.e. the great majority) are likely at low risk of developing leukemia. The hypothesis can also be applied to chronic myelogenous leukemia and to young-at-exposure cases of acute myelogenous leukemia.     

The effect of dose rate on radiation-induced neoplastic transformation in vitro by low doses of low-LET radiation

The dependence of the incidence of radiation-induced cancer on the dose rate of the radiation exposure is a question of considerable importance to the estimation of risk of cancer induction by low-dose-rate radiation. Currently a dose and dose-rate effectiveness factor (DDREF) is used to convert high-dose-rate risk estimates to low dose rates. In this study, the end point of neoplastic transformation in vitro has been used to explore this question. It has been shown previously that for low doses of low-LET radiation delivered at high dose rates, there is a suppression of neoplastic transformation frequency at doses less than around 100 mGy. In the present study, dose-response curves up to a total dose of 1000 mGy have been generated for photons from (125)I decay (approximately 30 keV) delivered at doses rates of 0.19, 0.47, 0.91 and 1.9 mGy/min. The results indicate that at dose rates of 1.9 and 0.91 mGy/min the slope of the induction curve is about 1.5 times less than that measured at high dose rate in previous studies with a similar quality of radiation (28 kVp mammographic energy X rays). In the dose region of 0 to 100 mGy, the data were equally well fitted by a threshold or linear no-threshold model. At dose rates of 0.19 and 0.47 mGy/min there was no induction of transformation even at doses up to 1000 mGy, and there was evidence for a possible suppressive effect. These results show that for this in vitro end point the DDREF is very dependent on dose rate and at very low doses and dose rates approaches infinity. The relative risks for the in vitro data compare well with those from epidemiological studies of breast cancer induction by low- and high-dose-rate radiation.     

Effects of low level radiation upon the hematopoietic stem cell: Implications for leukemogenesis

Summary These studies have addressed firstly the effect of single small doses of x-rays upon murine hematopoietic stem cells to obtain a better estimate of theD _q . It is small, of the order of 20 rad.Secondly, a dose fractionation schedule that does not kill or perturb the kinetics of hemopoietic cell proliferation was sought in order to investigate the leukemogenic potential of low level radiation upon an unperturbed hemopoietic system. Doses used by others in past radiation leukemogenesis studies clearly perturb hemopoiesis and kill a detectable fraction of stem cells. The studies reported herein show that 1.25 rad every day decrease the CFU-S content of bone marrow by the time 80 rads are accumulated. Higher daily doses as used in published studies on radiation leukemogenesis produce greater effects.Studies on the effect of 0.5, 1.0, 2.0, and 3.0 rad 3 times per week are under way. Two rad 3 times per week produced a modest decrease in CFU-S content of bone marrow after an accumulation of 68 rad. With 3.0 rad 3 times per week an accumulation of 102 rad produced a significant decrease in CFU-S content of bone marrow. Dose fractionation at 0.5 and 1.0 rad 3 times per week has not produced a CFU-S depression after accumulation of 17 and 34 rad.Radiation leukemogenesis studies published to date have utilized single doses and chronic exposure schedules that probably have significantly perturbed the kinetics of hematopoietic stem cells. Whether radiation will produce leukemia in animal models with dose schedules that do not perturb kinetics of hematopoietic stem cells remains to be seen.Dedicated to Prof. L.E. Feinendegen on the occasion of his 60th birthdayResearch supported by the U.S. Department of Energy under contract DE-ACO2-7 6CH00016. Accordingly, the U.S. government retains a nonexclusive, royalty-free license to publish or reproduce the published form of this contribution, or allow others to do so, for U.S. government purpose     

Biological dosimetry for astronauts: a real challenge

Manned space missions recently increased in number and duration, thus it became important to estimate the biological risks encountered by astronauts. They are exposed to cosmic and galactic rays, a complex mixture of different radiations. In addition to the measurements realized by physical dosimeters, it becomes essential to estimate real biologically effective doses and compare them to physical doses. Biological dosimetry of radiation exposures has been widely performed using cytogenetic analysis of chromosomes. This approach has been used for many years in order to estimate absorbed doses in accidental or chronic overexposures of humans. In addition to conventional techniques (Giemsa or FPG staining, R- or G-banding), faster and accurate means of analysis have been developed (fluorescence in situ hybridization [FISH] painting). As results accumulate, it appears that strong interindividual variability exists in the basal level of aberrations. Moreover, some aberrations such as translocations exhibit a high background level. Radiation exposures seem to induce variability between individual responses. Its extent strongly differs with the mode of exposure, the doses delivered, the kind of radiation, and the cytogenetic method used. This paper aims to review the factors that may influence the reliability of cytogenetic dosimetry. The emphasis is on the exposure to high linear energy transfer (LET) particles in space as recent studies demonstrated interindividual variations in doses estimated from aberration analysis after long-term space missions. In addition to the problem of dose estimates, the heterogeneity of cosmic radiation raises questions relating to the real numbers of damaged cells in an individual, and potential long-term risks. Actually, densely ionizing particles are extremely potent to induce late chromosomal instability, and again, interindividual variability exists in the expression of damage.     

Selenium as an adjuvant for modification of radiation response

Ionizing radiation plays a central role in several medical and industrial purposes. In spite of the beneficial effects of ionizing radiation, there are some concerns related to accidental exposure that could pose a threat to the lives of exposed people. This issue is also very critical for triage of injured people in a possible terror event or nuclear disaster. The most common side effects of ionizing radiation are experienced in cancer patients who had undergone radiotherapy. For complete eradication of tumors, there is a need for high doses of ionizing radiation. However, these high doses lead to severe toxicities in adjacent organs. Management of normal tissue toxicity may be achieved via modulation of radiation responses in both normal and malignant cells. It has been suggested that treatment of patients with some adjuvant agents may be useful for amelioration of radiation toxicity or sensitization of tumor cells. However, there are always some concerns for possible severe toxicities and protection of tumor cells, which in turn affect radiotherapy outcomes. Selenium is a trace element in the body that has shown potent antioxidant and radioprotective effects for many years. Selenium can potently stimulate antioxidant defense of cells, especially via upregulation of glutathione (GSH) level and glutathione peroxidase activity. Some studies in recent years have shown that selenium is able to mitigate radiation toxicity when administered after exposure. These studies suggest that selenium may be a useful radiomitigator for an accidental radiation event. Molecular and cellular studies have revealed that selenium protects different normal cells against radiation, while it may sensitize tumor cells. These differential effects of selenium have also been revealed in some clinical studies. In the present study, we aimed to review the radiomitigative and radioprotective effects of selenium on normal cells/tissues, as well as its radiosensitive effect on cancer cells.