Endothelial dysfunction in rectal cancer patients chronically exposed to ionizing radiation.

We sought to identify the features of endothelial function in rectal cancer patients who were exposed to chronic ionizing radiation from a nuclear test site in Kazakhstan. We examined 146 individuals, 76 of whom were rectal cancer patients. The existence of a complex of disturbances of the endothelium and hemostasis systems in patients vs non-patients was revealed. Endothelial dysfunction was expressed as an increase of nitric oxide (NO) production along with decreases in vasodilatation function, and increased levels of von Willebrand factor in blood, along with an increase in the number of circulating endotheliocytes. Significant correlations between indicators of endothelial function and vascular-platelet hemostasis were observed. These changes and their interrelations were expressed more strongly in the patients who lived in the contaminated area around the nuclear test site. Such patients could have an increased risk of thrombosis and other complications after the treatment of a malignant neoplasm.

Serum interleukin-6 associated with hepatocellular carcinoma risk: a nested case-control study.

Inflammatory markers have been associated with increased risk of several cancers, including colon, lung, breast and liver, but the evidence is inconsistent. We conducted a nested case-control study in the longitudinal cohort of atomic-bomb survivors. The study included 224 hepatocellular carcinoma (HCC) cases and 644 controls individually matched to cases on gender, age, city and time and method of serum storage, and countermatched on radiation dose. We measured C-reactive protein (CRP) and interleukin (IL)-6 using stored sera obtained within 6 years before HCC diagnosis from 188 HCC cases and 605 controls with adequate volumes of donated blood. Analyses with adjustment for hepatitis virus infection, alcohol consumption, smoking habit, body mass index (BMI) and radiation dose showed that relative risk (RR) of HCC [95% confidence interval (CI)] in the highest tertile of CRP levels was 1.94 (0.72-5.51) compared to the lowest tertile (p = 0.20). RR of HCC (95% CI) in the highest tertile of IL-6 levels was 5.12 (1.54-20.1) compared to the lowest tertile (p = 0.007). Among subjects with BMI > 25.0 kg/m(2) , a stronger association was found between a 1-standard deviation (SD) increase in log IL-6 and HCC risk compared to subjects in the middle quintile of BMI (21.3-22.9 kg/m(2) ), resulting in adjusted RR (95% CI) of 3.09 (1.78-5.81; p = 0.015). The results indicate that higher serum levels of IL-6 are associated with increased HCC risk, independently of hepatitis virus infection, lifestyle-related factors and radiation exposure. The association is especially pronounced among subjects with obesity.

The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells.

PURPOSE: Severe treatment-related lymphopenia (TRL) occurs in 40% of patients with high grade gliomas (HGG) receiving glucocorticoids, temozolomide, and radiation. This occurs following radiation, persists for months, and is associated with reduced survival. As all three treatment modalities are lymphotoxic, this study was conducted to estimate the radiation dose that lymphocytes receive passing through the radiation field and if this could explain the observed TRL. MATERIALS AND METHODS: A typical glioblastoma plan (8-cm tumor, 60 Gy/30 fractions) was constructed using the Pinnacle™ radiation planning system. Radiation doses to circulating cells (DCC) were analyzed using MatLab™. The primary endpoints were mean DCC and percent of circulating cells receiving ≥0.5 Gy. The model was also used to study how changes in target volumes (PTV), dose rates, and delivery techniques affect DCC. RESULTS: The modeling determined that while a single radiation fraction delivered 0.5 Gy to 5% of circulating cells, after 30 fractions 99% of circulating blood had received ≥0.5 Gy. The mean DCC was 2.2 Gy and was similar for IMRT, 3D-conformal techniques, and different dose rates. Major changes in PTV size affected mean DCC and percent of circulating cells receiving ≥0.5 Gy. CONCLUSIONS: Standard treatment plans for brain tumors deliver potentially lymphotoxic radiation doses to the entire circulating blood pool. Altering dose rates or delivery techniques are unlikely to significantly affect DCC by the end of treatment. Novel approaches are needed to limit radiation to circulating lymphocytes given the association of lymphopenia with poorer survival in patients with HGG.

Solitary plasmacytomas: outcome and prognostic factors after definitive radiation therapy.

BACKGROUND: The objective of this study was to review the outcome of patients with solitary plasmacytoma (SP) after definitive radiation therapy. METHODS: The authors retrospectively reviewed 84 patients with SP who were diagnosed and treated at The University of Texas MD Anderson Cancer Center during 1988 to 2008. The impact of tumor anatomic site, tumor size, and the presence of serum and urinary paraprotein at diagnosis was assessed on local control, survival, and the risk of developing multiple myeloma (MM). RESULTS: Fifty-nine patients (70%) had bone SP, and 25 patients (30%) had extramedullary SP. Serum paraprotein was present in 39 patients (46%). The median radiation dose was 45 grays (Gy) (range, 36-53.4 Gy). Local control was achieved in 77 patients (92%). Neither radiation dose nor tumor size predicted local control. The 5-year rate of progression to MM was 47% and was higher for patients with bone SP (56% vs 30% for extramedullary SP; P = .021), and patients who had serum paraprotein detected at diagnosis (60% vs 39%; P = .016). On univariate analysis, patients aged <60 years and men had higher rates of progression to MM, although the differences were not significant (P = .048 and P = .29, respectively). Multivariate analysis revealed that bone location and serum protein at diagnosis were associated statistically with progression to MM. The 5-year overall survival rate for the entire patient cohort was 78%, and no difference was observed between patients who had bone SP versus extramedullary SP (76% vs 85%, respectively; P = .274). CONCLUSIONS: The current results indicated that definitive radiation therapy for SP can provide excellent local control. Progression to MM remains the main problem and is more common among patients with bone SP and those who have serum paraprotein detected at diagnosis.

Success of the postoperative 131I therapy in young Belarusian patients with differentiated thyroid cancer after Chernobyl depends on the radiation absorbed dose to the blood and the thyroglobulin level.

PURPOSE: Differentiated thyroid carcinoma (DTC) in children and young adults is rare but often aggressive and in an advanced stage at diagnosis. In a cohort of young Belarusian patients with advanced DTC after Chernobyl we retrospectively studied parameters influencing the success of the postoperative (131)I therapy. METHODS: Included in the study were 136 patients (83 female, 53 male; median age 14.3 years, range 9.4-22.8 years) who had had total thyroidectomy in Belarus and subsequent (131)I therapy and follow-up in Germany. Of the 136 patients, 34 were classified as M1 and 102 as M0 (N0 1, N1 101). The median weight-adjusted (131)I activity administered after thyroid hormone withdrawal was 52 MBq/kg (range 24-74 MBq/kg). TNM stage, gender, administered activity, whole-body residence time and blood dose during ablation, Tg and TSH levels, date, and age at time of treatment were tested for their effect on the rate of complete remission (CR). CR was defined as a negative scan and a stimulated Tg level of <1 ng/ml at follow-up. RESULTS: CR was observed in 1 of 34 M1 and in 51 of 102 M0 patients after the first treatment. Multivariate analysis in the M0 group identified the Tg level (P < 0.0001 for log(Tg)) and the radiation absorbed dose to the blood (P < 0.001) as independent determinants; all other parameters were unimportant (P > 0.3). The regression model was able to correctly predict CR in 82 of 102 patients (80.4%). CONCLUSION: In children and young adults with advanced DTC, the rate of CR after postoperative (131)I therapy is dependent on the preablative Tg level and the radiation absorbed dose to the blood. Though the present results must be confirmed in a prospective study, they imply that preablative dosimetry may improve rates of CR.

IDENTIFICATION OF NOVEL BIOMARKERS FOR LUNG CANCER RISK IN HIGH LEVELS OF RADON BY PROTEOMICS: A PILOT STUDY.

Radon is the second most important risk factor for lung cancer after tobacco smoking. In Chiang Mai, Thailand, the values of indoor radon activity concentrations are considerably higher than global average values and it is a highest level among East Asian countries. The aim of our study is to identify novel biomarkers for lung cancer risk in high radon areas using a proteomic approach. In our transitional study, a total of 81 participants of non-smokers were examined, consist of 25 lung cancer patients (LC), 16 healthy controls from low levels of natural radiation areas (LLNRA) and 40 healthy controls from high levels of natural radiation areas (HLNRA). The results showed that a total of 799 differentially expressed proteins were identified. Among these, a total of 25 proteins were observed in both LC and HLNRA, but not in LINRA. Owing to the results obtained from this study, we also point out the research direction regarding the validation of some new candidate protein as a biomarker to screen population with high risk for lung cancer in the area with high levels of radon.

Discovering clinical biomarkers of ionizing radiation exposure with serum proteomic analysis.

In this study, we sought to explore the merit of proteomic profiling strategies in patients with cancer before and during radiotherapy in an effort to discover clinical biomarkers of radiation exposure. Patients with a diagnosis of cancer provided informed consent for enrollment on a study permitting the collection of serum immediately before and during a course of radiation therapy. High-resolution surface-enhanced laser desorption and ionization-time of flight (SELDI-TOF) mass spectrometry (MS) was used to generate high-throughput proteomic profiles of unfractionated serum samples using an immobilized metal ion-affinity chromatography nickel-affinity chip surface. Resultant proteomic profiles were analyzed for unique biomarker signatures using supervised classification techniques. MS-based protein identification was then done on pooled sera in an effort to begin to identify specific protein fragments that are altered with radiation exposure. Sixty-eight patients with a wide range of diagnoses and radiation treatment plans provided serum samples both before and during ionizing radiation exposure. Computer-based analyses of the SELDI protein spectra could distinguish unexposed from radiation-exposed patient samples with 91% to 100% sensitivity and 97% to 100% specificity using various classifier models. The method also showed an ability to distinguish high from low dose-volume levels of exposure with a sensitivity of 83% to 100% and specificity of 91% to 100%. Using direct identity techniques of albumin-bound peptides, known to underpin the SELDI-TOF fingerprints, 23 protein fragments/peptides were uniquely detected in the radiation exposure group, including an interleukin-6 precursor protein. The composition of proteins in serum seems to change with ionizing radiation exposure. Proteomic analysis for the discovery of clinical biomarkers of radiation exposure warrants further study.

Bioavailable serum estradiol may alter radiation risk of postmenopausal breast cancer: a nested case-control study.

PURPOSE: Ionizing radiation and high levels of circulating estradiol are known breast cancer carcinogens. We investigated the risk of first primary postmenopausal breast cancer in relation to the combined effects of whole-body ionizing radiation exposure and prediagnostic levels of postmenopausal sex hormones, particularly bioavailable estradiol (bE2). MATERIALS AND METHODS: A nested case-control study of 57 incident breast cancer cases matched with 110 controls among atomic bomb survivors. Joint effects of breast radiation dose and circulating levels of sex hormones were assessed using binary regression and path analysis. RESULTS AND CONCLUSION: Radiation exposure, higher levels of bE2, testosterone and progesterone, and established reproductive risk factors were positively associated with postmenopausal breast cancer risk. A test for mediation of the effect of radiation via bE2 level suggested a small (14%) but significant mediation (p = 0.004). The estimated interaction between radiation and bE2 was large but not significant (interaction = 3.86; p = 0.32). There is accumulating evidence that ionizing radiation not only damages DNA but also alters other organ systems. While caution is needed, some portion of the radiation risk of postmenopausal breast cancer appeared to be mediated through bE2 levels, which may be evidence for cancer risks due to both direct and indirect effects of radiation.

Screening of biomarkers for liver adenoma in low-dose-rate γ-ray-irradiated mice.

PURPOSE: Chronic low-dose-rate (20 mGy/day) γ-irradiation increases the incidence of hepatocellular adenomas (HCA) in female B6C3F1 mice. The purpose of this study is to identify potential serum biomarkers for these HCAs by a new approach. MATERIAL AND METHODS: Microarray analysis were performed to compare the gene expression profiles of HCAs from mice exposed to low-dose-rate γ-rays with those of normal livers from non-irradiated mice. From the differentially expressed genes, those for possibly secretory proteins were selected. Then, the levels of the proteins in sera were analysed by ELISA. RESULTS: Microarray analysis identified 4181 genes differentially expressed in HCAs (>2.0-fold). From these genes, those for α-fetoprotein (Afp), α-1B-glycoprotein (A1bg) and serine peptidase inhibitor Kazal type-3 (Spink3) were selected as the genes for candidate proteins. ELISA revealed that the levels of Afp and A1bg proteins in sera significantly increased and decreased, respectively, in low-dose-rate irradiated mice with HCAs and also same tendency was observed in human patients with hepatocellular carcinomas. CONCLUSION: These results indicate that A1bg could be a new serum biomarker for liver tumor. This new approach of using microarray to select genes for secretory proteins is useful for prediction of novel tumor markers in sera.

Role of biomarkers in predicting the occurrence of thyroid neoplasms in radiation-exposed children.

With increasing numbers of childhood cancer survivors who were treated with radiation, there is a need to evaluate potential biomarkers that could signal an increased risk of developing thyroid cancer. We aimed to examine the relationships between thyrotropin and thyroglobulin levels and the risk of developing thyroid nodules and cancer in a cohort of radiation-exposed children. 764 subjects who were irradiated in the neck area as children were examined and followed for up to 25 years. All subjects underwent a clinical examination, measurements of thyrotropin, thyroglobulin levels and thyroid imaging. At baseline, 216 subjects had thyroid nodules and 548 did not. Of those with nodules, 176 underwent surgery with 55 confirmed thyroid cancers. During the follow-up, 147 subjects developed thyroid nodules including 22 with thyroid cancer. Thyroglobulin levels were higher in subjects with prevalent thyroid nodules (26.1 ng/mL vs 9.37 ng/mL; P < 0.001) and in those who had an initial normal examination but later developed thyroid nodules (11.2 ng/mL vs 8.87 ng/mL; P = 0.017). There was no relationship between baseline thyrotropin levels and the prevalent presence or absence of thyroid nodules, whether a prevalent neoplasm was benign or malignant, subsequent development of thyroid nodules during follow-up or whether an incident nodule was benign or malignant. In conclusion, in radiation-exposed children, higher thyroglobulin levels indicated an increased risk of developing thyroid nodules but did not differentiate between benign and malignant neoplasms. There was no association between the baseline TSH level and the risk of developing thyroid nodules or cancer.

Individual variation of somatic gene mutability in relation to cancer susceptibility: prospective study on erythrocyte glycophorin a gene mutations of atomic bomb survivors.

It has previously been reported that hemizygous mutant fraction (Mf) at the glycophorin A (GPA) locus in erythrocytes increased with radiation dose in heterozygotes among Hiroshima and Nagasaki atomic bomb survivors. In the present study, we analyzed the relationship between GPA Mf and cancer risk using newly developed cancers among previously cancer-free subjects whose GPA Mf had been measured between 1988 and 1996. Among 1,723 survivors (1,117 in Hiroshima and 606 in Nagasaki), we identified 186 subjects who developed a first cancer by the end of 2000. We compared the radiation dose responses of GPA Mf between cancer and cancer-free groups using a linear-quadratic model fit by multiple regression analysis in combination with age, sex, and city. The slope of the GPA Mf dose-response curve was significantly higher in the cancer group than in the cancer-free group among Hiroshima subjects. Moreover, no significant difference of GPA Mf between cancer and cancer-free groups was found in unexposed controls in the two cities. The same conclusions were obtained using a linear dose-response model and by further analysis using Cox regression of cancer incidence. These findings suggest that there might be interindividual variation in mutability of somatic genes and that Hiroshima survivors who have higher mutability in response to radiation exposure would be expected to have a higher probability of suffering radiation-related cancer.

Synergism of estrogens and X-rays in mammary carcinogenesis in female ACI rats.

A previously demonstrated synergistic interaction between diethylstilbestrol (DES) and radiation on rat mammary carcinogenesis was extended to another estrogen, 17-ethinylestradiol (EE2). These newly reported results with EE2 demonstrated that the previously reported synergistic interaction between DES and radiation is not confined to just DES. Instead, these new results implied that the synergistic interaction is a synergistic interaction between the estrogenic activity of DES and radiation on rat mammary carcinogenesis. Female inbred ACI rats were used. By the end of the experiment, no neoplasia was detected in rats bearing cholesterol pellets, with and without X-ray exposure. No significant tumor data were obtained from rats treated with 0.1 me EE2, with and without X-rays. Approximately 50% of the rats treated with DES and approximately 90% of the rats treated with 1 mg EE2 had 1 or more mammary adenocarcinomas (MAC). X-rays synergistically increased the number of MAC per rat in the groups implanted with DES or 1 mg EE2. X-rays also increased the trend toward earlier increased incidence of rats with MAC as compared to rats treated with estrogens only. All rats treated with DES and 1 mg EE2 had pituitary tumors. The mean weight of the pituitary tumors in the groups treated with 1 mg EE2 was approximately 1.5 times that of the groups treated with DES. Mean terminal plasma prolactin levels for rats treated with 1 mg EE2 or DES were, respectively, 17.5 and 9.5 times control values.

Androgen-mediated development of irradiation-induced thyroid tumors in rats: dependence on animal age during interval of androgen replacement in castrated males.

When male Long-Evans rats at age 8 weeks were radiation treated (40 microCi Na131I), thyroid follicular adenomas and carcinomas were observed at age 24 months with a high incidence of 94%. Castration of males prior to irradiation significantly reduced this tumor incidence to 60%. When testosterone (T) was replaced in castrated, irradiated male rats, differentially increased incidences of thyroid tumors occurred, depending on the time interval for hormone replacement. Immediate (age 2-6 mo) or early (age 6-12 mo) T replacement at approximate physiologic levels led to thyroid follicular tumor incidences of 100 and 82%, respectively, whereas intermediate (12-18 mo) or late (18-24 mo) T treatment led to only 70 and 73% incidences, respectively. Continuous T replacement (2-24 mo) in castrated irradiated male rats raised thyroid tumor incidence to 100%. Since elevated thyroid-stimulating hormone (TSH) is a reported requisite for development of radiation-associated thyroid tumors, the effects of T on serum TSH levels were examined. Mean serum TSH values in all irradiated animal groups were significantly elevated above age-matched nonirradiated animals at 6, 12, 18, and 24 months. Serum TSH levels were higher in continuous T-replaced irradiated castrates than in intact, irradiated males, whereas such intact male TSH levels were greater than those for irradiated castrates without T treatment. Interval T replacement in castrated male rats was generally associated with increased serum TSH levels during the treatment interval and with lowered TSH levels after discontinuation of T treatment, particularly in irradiated rats. However, when irradiated, castrated males received late T replacement (age 18-24 mo), there was no elevation of TSH at the end of the treatment interval. Thus an indirect effect of T via early stimulation of TSH may be at least partly responsible for the high incidence of irradiation-induced thyroid tumors in rats.

Treatment-induced changes in tumor oxygenation predict photodynamic therapy outcome.

Photodynamic therapy (PDT) requires oxygen to cause tumor damage, yet therapy itself can deplete or enhance tumor oxygenation. In the present work we measured the PDT-induced change in tumor oxygenation and explored its utility for predicting long-term response to treatment. The tissue hemoglobin oxygen saturation (SO(2)) of murine tumors was noninvasively measured by broadband diffuse reflectance spectroscopy. In initial validation studies, the oxyhemoglobin dissociation curve for mouse blood was accurately recreated based on measurements during deoxygenation of a tissue phantom of mouse erythrocytes. In vivo studies exhibited excellent correlation between carbogen-induced changes in SO(2) and pO(2) of radiation-induced fibrosarcoma tumors measured by reflectance spectroscopy and the Eppendorf pO(2) histograph, respectively. In PDT studies radiation-induced fibrosarcoma tumor SO(2) was measured immediately before and after Photofrin-PDT (135 J/cm(2), 38 mW/cm(2)). Animals were subsequently followed for tumor growth to a volume of 400 mm(3) (time-to-400 mm(3)) or the presence of tumor cure (no tumor growth at 90 days after treatment). In animals that recurred, the PDT-induced change in tumor SO(2), i.e., relative-SO(2) (SO(2) after PDT/SO(2) before PDT) was positively correlated with treatment durability (time-to-400 mm(3)). The predictive value of relative-SO(2) was confirmed in a second group of animals with enhanced pre-PDT oxygenation due to carbogen breathing. Furthermore, when all of the animals were considered (those that recurred and those that were cured) a highly significant association was found between increasing relative-SO(2) and increasing probability of survival, i.e., absence of recurrence. As independent variables, the SO(2) after PDT, the pre-PDT tumor volume, and light penetration depth all failed to predict response. As an independent variable, the SO(2) before PDT demonstrated a weak negative association with treatment durability; this association was driven by a correlation between decreasing pre-PDT SO(2) and increasing relative-SO(2). These data suggest that monitoring of PDT-induced changes in tumor oxygenation may be a valuable prognostic indicator.

Prospective serum thyroglobulin measurements in assessing the risk of developing thyroid nodules in patients exposed to childhood neck irradiation.

We examined 327 patients with a history of cervical radiation treatment for benign conditions and followed them for an average of 5.6 yr. These patients were selected because they initially had normal examinations and normal serum thyroglobulin levels. Of the 327 patients, 48 developed thyroid nodules, and an additional 30 had other clinical changes in their thyroids. Serum thyroglobulin increased by 4.0 +/- 0.6 (+/- SEM) ng/ml in those who remained normal, by 13.4 +/- 5.2 ng/ml in those who were no longer normal, and by 17.1 +/- 8.2 ng/ml in those who developed nodules. We conclude that increasing levels of serum thyroglobulin identify patients who should be examined and followed more carefully for thyroid nodules and thyroid cancer.

Serum TSH, thyroglobulin, and thyroidal disorders in atomic bomb survivors exposed in youth: 30-year follow-up study.

Follow-up examinations to determine the frequency of thyroidal disorders were conducted by the Radiation Effects Research Foundation (RERF) on individuals in Hiroshima and Nagasaki who were less than 20 yr of age at the time of exposure to the atomic bomb. Concentrations of serum thyroid stimulating hormone (TSH), thyroglobulin (TG), and anti-TG antibody 30 yr after exposure were also determined. Nontoxic uninodular goiter was found in 13 cases of the 100 + rad exposed group (n = 477) and in three cases of the nonexposed group (n = 501). The prevalence in the 100+ rad exposed group was significantly higher (chi-squared = 6.584, p less than 0.01). Thyroid cancer was found in eight exposed cases, all of whom were in the 100+ rad group, and the prevalence was significantly greater (chi-squared = 7.919, p less than 0.01). Regardless of the presence or absence of thyroid disorders, serum TSH and TG levels were not statistically different between the 100 rad + exposed and nonexposed groups. Although hypothyroidism was found in 23 of the total cases, there was no correlation between its development and exposure to ionizing irradiation.

Effect of vitamin A on lung tumorigenesis in irradiated and unirradiated strain A mice.

The effect of vitamin A (retinyl acetate) on lung tumor development in strain A mice exposed to radiation was assessed. Four groups of 75 mice were utilized. Two groups were fed a low vitamin A diet (less than 100 IU/100 g diet) and the other 2 were fed a high vitamin A diet (800 IU/100 g diet). After 2 weeks one group maintained on the high vitamin A diet and one group maintained on the low vitamin A diet were given an acute dose of 500 rad of gamma radiation to the thoracic region. Circulating levels of plasma vitamin A in all 4 groups of mice were monitored. A difference in circulating vitamin A in the mice maintained on high and low vitamin A diet became evident by 20 weeks and continued for the duration of the experiment. Mice were killed 18, 26 and 40 weeks post-irradiation, their lungs were removed and the number of surface adenomas were counted. There was a significant increase in the number of mice bearing lung tumors and the mean number of lung tumors per mouse in the irradiated group maintained on the high vitamin A diet at 40 weeks post-irradiation as compared to the irradiated group maintained on a low vitamin A diet. Under the conditions of this experiment the development of pulmonary adenomas in irradiated strain A mice appears to relate directly to circulating levels of vitamin A.

Oestrogen receptors in rat mammary tissue and plasma concentrations of prolactin during mammary carcinogenesis induced by oestrogen and ionizing radiation.

Female-Sprague-Dawley rats received a subcutaneous implant containing 2 mg oestradiol at the age of 7 weeks. One week later half of the rats treated with oestrogen and half of the rats in an untreated control group were irradiated with 2 Gy (200 rad) of X-rays. The content of oestrogen receptor of the mammary tissue and the concentration of prolactin in the plasma were studied at intervals of 2 months for a period of 14 months after this treatment. Oestrogen treatment resulted in a decrease in the content of oestrogen receptors in the mammary tissue of both irradiated and non-irradiated rats. In oestrogen-treated rats, plasma prolactin was raised 10-50 times and pituitary tumours were observed. Radiation had no additional effect on the oestrogen-receptor content of mammary tissue or the concentration of plasma prolactin. The changes in the oestrogen-receptor content of mammary tissue and the prolactin concentration of plasma preceded the development of mammary tumours. It is suggested that the synergistic action of oestrogen and radiation on rat mammary tumour development is the result of a stimulation by oestrogen and/or prolactin of the sensitivity of the mammary gland to ionizing radiation.