Effect of low-level irradiation on incidence rate and development of malignant neoplasms

Low-level irradiation (1.2-2.4 cGy, dose-rate 0.6 cGy/day) leads to a significant acceleration of the development of spontaneous leukosis in AKR mice: decrease in the average and the maximum life-span of animals leukosis-carriers (by 20 and 120 days, respectively) and an increase in the leukosis incidence rate (%). The introduction of antioxidant phenozan (beta-(4-hydroxy-3,5-ditertbutylphenyl) propionic acid) results in a considerable antileukosis effect: the average life-span increases by more than 40 days and the leukosis incidence rate decreases by 6%.     

Spontaneous leukosis as a model for an investigation of low and very low physical and physico-chemical effects on oncological process

Kinetic investigation of spontaneous leukosis in AKR mice have been carried in connection with a number of indices: changes in the mass of principal organs of the immune systems (thymus, spleen, lymphatic nodes), liver, alterations of haematological data (the sum of leukocytes, the percentage composition of blood cells, the quantity of undifferentiated cells), changes of physico-chemical conditions in cells (NMR-investigation). The dynamics of some of these indices and also life-spans of animals with leukosis after irradiation with doses 1.2-2.4 cGy (dose-rate 0.6 cGy/day) have been investigated. The enhancement of the frequency of leukosis and shortening the average and maximum life-spans of irradiated mice has been found.     

Tissue Culture Studies in Bovine Leukosis

By examining cover slips stained at regular intervals the development of primary lymph node tissue cultures from 2 cases of juvenile bovine leukosis and 2 “normal” foetuses was studied. Secondly, comparisons were made between cell lines prepared from 23 bovines — “normal” animals and foetuses, cases of adult leukosis, juvenile leukosis and skin leukosis — with respect to susceptibility to infection with interferon sensitive viruses (VSV and PRV) and/or growth rate in the presence of sera from “normal” and leukotic animals. Nuclear budding, nuclear fragmentation, lymphocyte adsorption and giant cell formation were observed — though to a much greater extent in cultures prepared from the leukosis animals — in all 4 cases studied. No indications of different susceptibility for the test virus infections appeared between cell lines prepared from “normal” and leukotic animals. The growth rate of the cell lines seemed similar irrespective of the kind of serum used.     

Changes in levels of p53 protein, immunoglobulin L-chains, and iron complexes in mice of leukosis strain AKR following low dose irradiation

Changes in the content of protein p53 (regulator of the cell cycle) L-chains of immunoglobulins, and iron complexes (Fe2+) during the development of spontaneous leukosis in AKR mice and upon irradiation of animals with a dose of 1.2 cGy were studied by ESR spectroscopy, electrophoresis, and immunoblotting. It was found that irradiation leads to an increase in the incidence of leukoses in males by 7% and a decrease in life duration of females. A decrease in the content of protein p53 and L-chains in immunoglobulins in males and females was observed; however, in females, the decreases was less pronounced because the content of these proteins in females is naturally decreased. In mice irradiated with low doses at the age of three- to four months, a decrease in the amount of iron complexes at a later age (seven- to eight months) was registered. These data suggest that there is a relationship between the induction of protein p53 and the content of immunoglobulin L-chains in the blood serum of animals.     

P53 under low-intensity inluence of physical and chemical nature (ionizing radiation and antioxidant)

It was found that low-intensity ionizing radiation and the antioxidant fenozan at a low concentration (10(-14) M) produce opposite effects on the content of protein p53 in the blood serum of mice. Thus, low-intensity gamma-irradiation of AKR mice with a dose of 1.2 cGy (0.6 cGy per day) led to a decrease in the content of p53 and acceleration of leukosis, whereas fenozan, which has membranolytic and radioprotective properties, when injected intramuscularly to F1 mice (CBA + c57 black) increased the content of p53. However, the dynamics of the activation of protein p53 depended on the concentration of fenozan (10(-4) or 10(-14)), which may be due to the difference in its binding to the membrane and the changes in its antioxidative properties depending on concentration.     

Radiosensitizing and damaging effect of hyperthermia on different biological systems. Radiosensitizing and damaging effect of hyperthermia on cells of mouse La leukemia

When mouse leukosis cell suspensions were subjected to heating the survival rate of animals decreased exponentially with increasing time of heating. It is shown that the increase of temperature for 1 degree C in the range 40-45 degrees C is equivalent to a decrease in the heating time by a factor of approximately 2. The hyperthermia-induced increase in the radiosensitivity of leukosis cells was dependent upon a medium in which heating was performed.     

Characterization of radiation-induced emesis in the ferret

Forty-eight ferrets (Mustela putorius furo) were individually head-shielded and radiated with bilateral 60Co gamma radiation at 100 cGy min-1 at doses ranging between 49 and 601 cGy. The emetic threshold was observed at 69 cGy, the ED50 was calculated at 77 cGy, and 100% incidence of emesis occurred at 201 cGy. With increasing doses of radiation, the latency to first emesis after radiation decreased dramatically, whereas the duration of the prodromal period increased. Two other sets of experiments suggest that dopaminergic mechanisms play a minor role in radiation-induced emesis in the ferret. Twenty-two animals were injected either intravenously or subcutaneously with 30 to 300 micrograms/kg of apomorphine. Fewer than 50% of the animals vomited to 300 micrograms/kg apomorphine; central dopaminergic receptor activation was apparent at all doses. Another eight animals received 1 mg/kg domperidone prior to either 201 (n = 4) or 401 (n = 4) cGy radiation and their emetic responses were compared with NaCl-injected-irradiated controls (n = 8). At 201 cGy, domperidone significantly reduced only the total time in emetic behavior. At 401 cGy, domperidone had no salutary effect on radiation-induced emesis. The emetic responses of the ferret to radiation and apomorphine are compared with these responses in other vomiting species.     

Murine survival of lethal irradiation with the use of human umbilical cord blood.

We have found that human umbilical cord blood (HUCB) will routinely protect mice exposed to lethal levels of irradiation. At the end of 50 days, over seventy percent (70%) of mice injected with HUCB survived 900 cGy or irradiation, which produced 100% deaths in the uninjected control animals. Moreover, there was some evidence that human colony stimulating factors further improved survival. Anti-Natural Killer cell (NK) antibody was utilized along with HUCB in these studies, however, Anti-NK cell serum alone had no radioprotective effect in mice. The studies reported here suggest the possibility of utilizing HUCB for immediate protection of humans from lethal irradiation.     

Responses of the beagle to protracted irradiation. I. Effect of total dose and dose rate

The effects of protracted exposure to 60Co gamma rays on survival and tumor induction in the beagle were investigated. Total accumulated doses of 450, 1050, 1500, and 3000 cGy were given at rates of 3.8, 7.5, 12.8, and 26.3 cGy/day. Hazard models were used to identify trends in mortality associated with radiation exposure. The probability of an acute death (related to hematopoietic aplasia) was positively associated with the total dose received and the rate at which the dose was delivered. Once an animal survived the initial hematopoietic effects of radiation exposure, the risk of death from causes other than cancer, while elevated, was far less responsive than the neoplastic end points. No relationship between tumor or chronic nontumor deaths and dose rate could be identified. However, survival curves for tumor mortality did separate into a pattern clearly dependent on the accumulated dose.     

Changes in functional activity of the synthetic apparatus of rat thymocytes under acute and chronic gamma-irradiation

The changes in functional activity of rat thymocyte synthetic apparatus (synthetic activity) under acute (7.5 Gy) and continuous (dose rates 14.4 and 0.43 cGy/day) gamma-irradiation were studied by the fluorescent microspectral analysis. It has been shown that after the acute irradiation the changes in synthetic activity occurred in three main stages. The stages reflect the depression and activation of synthetic processes that is due to interphase and reproductive cell death and urgent recovery of thymus cellularity and secondary repopulating. Under continuous irradiation with a dose rate 14.4 cGy/day in long-term period both the decrease of thymocyte synthetic activity (in most animals) and activation (in the animals with pronounced symptoms of radiation damage) were observed. This reflects the depression processes in immune system and augmentation of immunoreactivity due to mass antigen influence of transformed cells and infectious agents on thymocytes. Under low dose ionizing irradiation (dose rate 0.43 cGy/day) the undulating changes in synthetic processes in thymus cells were observed. This depends on the recurrence of depression and recovery processes in the blood-forming tissue.     

Modifying effect of oxolinic acid on the radiation-induced hemorrhagic syndrome

The radioprotective effect of oxolinic acid (200 mg/kg) was studied in irradiated guinea pigs (3 Gy, 0.83 cGy/min) by the following criteria: survival rate, hemorrhage severity, and homeostasis disturbance. Oxolinic acid was found to decrease the death rate, severity of hemorrhage and the degree of thrombo- and leukopenia, and to reduce the injury to blood coagulation and vascular wall of irradiated animals.     

Effects of organic fluorosilicone compounds on the development of tumors in mice

The influence of new synthesized fluoro-silicium-organic complexes on the virus-induced Rauscher leukosis and cell-transferred MX-11 mouse sarcoma was studied. We also studied the cytotoxic effects of these complexes in vitro in the human CaOv cells. Two complexes from seven studied were cytotoxic for CaOv cells. Five complexes from seven studied diminished the mortality of animals with MX-11 tumors on the 27-th day of observation, but the total life duration of the animals in the experimental group was the same as in controls. One complex from seven studied increased the life duration of mice with MX-11 tumors. No effects were noted in relation to mice virus-induced Rauscher leukosis.     

Integration of bovine leukemia virus DNA in the genomes of bovine lymphosarcoma cells

Integration of bovine leukemia virus (BLV) in the genomes of infected cells was investigated in cattle with enzootic bovine leukosis (EBL) and sporadic bovine leukosis (SBL). Southern blot hybridization of BLV cDNA to Eco RI and Xba I restriction fragments of EBL tumor DNAs revealed that: 1) one to four or more copies of proviral DNA were integrated per genome; 2) the restriction pattern of the integrated proviral DNA was the same in two or three different tumors from the same animals; and 3) different patterns were observed among tumors from four different animals. These findings suggest the monoclonal origin of different tumors in an individual animal and the existence of multiple chromosomal integration sites of BLV provirus. DNAs from several SBL tumors were also analyzed with the same restriction enzymes, but with both representative and cDNA3'-enriched's of BLV RNA. No hybridization bands reactive with representative BLV cDNA could be detected, while several bands appeared to hybridize with cDNA3'-enriched.     

Preparation of dihydrocarminomycin and a comparison of its antitumor activity with the activity of carminomycin]

A dihydro derivative of karminomycin was prepared using chemical reduction with potassium boron hydride. When dihydrokarminomycin was administered intravenously to healthy albino mice in a single dose it practically showed the same toxicity as karminomycin. However, unlike the latter dihydrokarminomycin induced the death of the animals at later periods of time. Studies on mice with transplantable tumours showed high antitumor activity of dihydrokarminomycin against lymphosarcoma L10-1, sarcoma 180, Garding-Passy melanoma, lymphoid leukosis L-1210 and lymphocytal leukosis P-388. In treatment of the mice with leukosis L-1210 and Garding-Passy melanoma dihydrokapminomycin was much inferior by its efficiency than karminomycin.     

Uptake of carbon monoxide by C3H mice following X irradiation of lung only or total-body irradiation with 60Co

Carbon monoxide uptake (Vco) and ventilation rate (VR) of C3H mice were determined at 14 weeks following either X irradiation of lungs only or total-body irradiation with 60Co at different dose rates. Following localized X irradiation of lung at 97 cGy/min there was a reduction in Vco, which was inversely related to radiation dose, with a small reduction below control levels being detected at 7 Gy, the lowest dose tested. An increase in VR could be detected only at doses of 11 Gy, or more. Another group of animals received 11.5 Gy total-body irradiation at either 26.2 or 4.85 cGy/min followed by transplantation with syngeneic bone marrow. Following total-body irradiation, Vco was significantly reduced by about 37% at the higher dose rate and 23% at the lower dose rate. In contrast, a trend toward elevated VR was detected only at the higher dose rate. The results indicate that Vco is a sensitive indicator of radiation-induced lung injury and that under the experimental conditions used Vco is a more sensitive indicator of radiation-induced lung injury in C3H mice than VR.     

Effect of external gamma radiation on shortening the life expectancy and rates of the formation of absorbed doses from incorporated 239Pu in dogs

External gamma irradiation of dogs with doses of 103.2 and 51.6 mC/kg combined with the effect of inhaled plutonium-239 accelerates the formation of absorbed doses in secondary organs of the radionuclide deposition by 41.7 and 2.4 times, respectively, whereas the dose of 25.8 mC/kg is ineffective. As estimated by the rate of 239Pu accumulation and by the life span shortening, the minimum effective and the maximum ineffective doses are 104.8 and 80.5 cGy and 89.2 and 79.2 cGy, respectively.     

Properties of DNA-dependent RNA-polymerase from spleens of mice infected with Rauscher leukemic virus]

The properties of RNA polymerases A, B and C isolated from the spleens of mice infected with Rauscher leukemic virus were studied. The solubilized RNA-polymerases A and B were purified 150--300-fold. The dynamic changes in the activities of all forms of RNA-polymerases at different stages of leukosis were studied. At the earliest steps of leukosis a 2-fold increase in the RNA-polymerase B activity followed by a 5-fold increase in the RNA-polymerase A activity was observed. At late stages of leukosis the activity of RNA-polymerase C also showed an increase. The properties of RNA-polymerases A and B from the spleens of virus-infected mice were compared to those of the controls. In leukemic tissues the specific activities of RNA-polymerases A and B were higher as compared to those of the enzymes isolated from the spleens of non-infected mice. However, no significant differences in the enzyme properties in normal and virus-infected animals were revealed. Dihydrorifampicine (200 mkg/ml) caused a 50% inhibition of RNA polymerase A in vitro but had no effect on the activities of RNA-polymerases B and C.     

Life shortening in mice exposed to fission neutrons and gamma rays. VIII. Exposures to continuous gamma radiation

Data are presented on the mean aftersurvival of male B6CF1 mice exposed for 22 h per day, 5 days per week, to 60Co gamma radiation at dose rates of 1.36 to 12.64 x 10(-3) cGy/min for 23 weeks or 1.36 to 6.32 x 10(-3) cGy/min for 59 weeks. For deaths from all causes, linear dose-response curves were obtained with slopes (days of life lost/cGy) of 0.158 +/- 0.016 and 0.077 +/- 0.002 for 23- and 59-week exposures, respectively. These values were not significantly altered when the analysis was restricted to those mice dying with tumors (92% of the total) or to those presumably dying from tumors (82% of the total). Analysis of mortality rates showed that about 90% of the radiation-specific excess mortality was tumor related. The 59-week exposure series induced only a small increase in the number of days of life lost/cGy/weekly fraction over that induced by 23 weeks of irradiation, 4.53 +/- 0.15 compared to 3.64 +/- 0.36 days lost/cGy/weekly fraction. This lower than expected value for 59 weeks of exposure may signal the approach to the final linear, additive, injury term postulated from earlier studies at this laboratory with low-dose-rate, daily, duration-of-life 60Co gamma irradiation.     

Carcinogenesis in laboratory mice after low doses of ionizing radiation

Experimental data on the incidence of solid tumors from various long-term mouse studies performed at the Casaccia laboratories over several years were reconsidered, limiting the analysis to the results available for doses equal to or less than 17 cGy of neutrons and 32 cGy of X rays since these dose limits are reasonably close to the generally accepted low-dose levels for high- and low-LET radiation (i.e. D(high-LET) < 5 cGy and D(low-LET) < 20 cGy, respectively). The following long-term experiments with BC3F1 mice were reviewed: (a) females treated with single doses of 1.5 MeV neutrons or 250 kVp X rays, (b) males treated with fractionated doses of fission neutrons, and (c) mice of both sexes irradiated in utero 17.5 days post coitus with single doses of fission neutrons or X rays. An experiment with CBA mice of both sexes treated with single doses of fission neutrons was also included in this study. Analysis was done on animals at risk; thus all incidences of tumor-bearing animals were expressed as the percentage excess incidence with respect to the controls. Ovarian tumors and other solid neoplasms were considered. The percentage frequencies and mean survival times of tumor-free mice were also recalculated. The results indicate the existence of a region at low doses where the final incidence of solid neoplasms is indistinguishable from the background incidence. These data reinforce the idea that at low doses the effectiveness of ionizing radiation in inducing solid neoplasms in laboratory mice is very low.     

Effects of low-dose neutrons applied at reduced dose rate on human melanoma cells

Human melanoma cells that are resistant to gamma rays were irradiated with 14 MeV neutrons given at low doses ranging from 5 cGy to 1.12 Gy at a very low dose rate of 0.8 mGy min(-1) or a moderate dose rate of 40 mGy min(-1). The biological effects of neutrons were studied by two different methods: a cell survival assay after a 14-day incubation and an analysis of chromosomal aberrations in metaphases collected 20 h after irradiation. Unusual features of the survival curve at very low dose rate were a marked increase in cell killing at 5 cGy followed by a plateau for survival from 10 to 32.5 cGy. The levels of induced chromosomal aberrations showed a similar increase for both dose rates at 7.5 cGy and the existence of a plateau at the very low dose rate from 15 to 30 cGy. The existence of a plateau suggests that a repair process after low-dose neutrons might be induced after a threshold dose of 5-7.5 cGy which compensates for induced damage from doses as high as 32.5 cGy. These findings may be of interest for understanding the relative biological effectiveness of neutrons and the effects of environmental low-dose irradiation.