Inverse Dose-rate Effect Research Articles

Ionizing radiation regulates expression of the c-jun protooncogene.

There is little known about the regulation of gene expression by ionizing radiation exposure. The present studies demonstrate transcriptional activation of a mammalian gene, the c-jun protooncogene, by x-rays. The c-jun gene encodes a component of the AP-1 protein complex and is important in early signaling events involved in various cellular functions. The increase in c-jun transcripts by ionizing radiation was time- and dose-dependent as determined by Northern blot analysis. Transcriptional run-on analysis demonstrated that ionizing radiation stimulates the rate of c-jun gene transcription. Furthermore, the half-life of c-jun RNA was prolonged in the absence of protein synthesis. These findings indicate that the increase in c-jun RNA observed after irradiation is regulated by transcriptional and posttranscriptional mechanisms. Moreover, the induction of c-jun by ionizing radiation was associated with an inverse dose rate effect in that decreasing the dose rate resulted in increased c-jun expression. The present results similarly demonstrate that ionizing radiation increases levels of c-fos transcripts as well as that of jun-B, another member of the jun family. Taken together, these results suggest a role for induction of early response genes in the pathophysiologic effects of ionizing radiation.

Radiobiological aspects of low dose rates in radioimmunotherapy

It is assumed that initial dose rates of 10–20 cGy/hour and total doses of 1500–2000 cGy, delivered with effective half-lives of a few days, are reasonable starting points for assessing the radiobiological effects of such low and declining dose rates. Such doses might kill 2 or 3 logs of cells out of the 9 or 10 required for tumor eradication; this is well known. The emphasis in this paper is on the change of effectiveness (per Gy) with change in dose rate. Biological effectiveness, in terms of log cell kill per Gy, will be less than that of higher dose rates because there is more time for repair of sublethal radiation injury. This loss in Relative Effectiveness, RE, is unlikely to exceed 20% in most types of tumor cell, compared with conventional external beam radiation schedules. Therefore, a tumor or metastic deposit that would require 60–70 Gy to sterilize it using conventional radiotherapy with 2 Gy fractions (or traditional radioactive implants at 50 cGy/hr) would require 70–84 Gy at the lower dose rates available from radioimmunotherapy. This is the major dose rate effect and so far we have ignored proliferation. In the dose-rate range of 10–300 cGy/hr in vitro, highly variable depending on type of cell, division might be prevented but not progression through the cell cycle. Additional cell kill is observed because cells accumulate in the radiosensitive G 2 phase; this is the inverse dose-rate effect. However, that range of dose rates comes from in vitro experiments where cells are doubling in number every 0.5 to 1 day. In vivo they double more slowly so it is possible that the unpredictable benefit of G 2 accumulation, or partial synchrony, could occur at lower dose rates than 10 cGy/hr in human tumors. The dose rates necessary to kill cells at exactly the rate they are proliferating (which of course would not alone eradicate tumors or metastases) can be calculated, if values are assumed for intrinsic radiosensitivity and doubling rate of cells. In median ranges, dose rates of 2–3 cGy/hr should just counteract proliferation. Higher dose rates, maintained for a few days, could cause 2 or 3 logs of cell kill which would be observed as partial regression, as has been reported clinically and in animal experiments.

Radiation induced lipid peroxidation in liposomes

Liposomes prepared from L-α-lecithin were irradiated to different doses of radiation (0–660 Gy) at the dose rate 1.109 Gy s -1. Lipid peroxidation was found to increase with radiation dose up to 330 Gy and decrease with dose beyond 330 Gy. This suggests that in low dose region (0–330 Gy) most of the energy deposited into liposomes is translated into damage. On the other hand energy deposited in higher dose region (396–660 Gy) may not have completely translated into damage and some part of it might have dissipated to recombination process of free radicals resulting into formation of relatively stable and unreactive molecular products. Observation with different concentrations of liposomes, inhibition of peroxidation by catalase, enhancement by Fe 2+-ions and inverse dose rate effect indicate indirectly the occurence of recombination processes. The decrease in lipid peroxidation might also be due to the avoidance of propagation step.

The Inverse Dose-rate Effect for Oncogenic Transformation by Neutrons and Charged Particles: A Plausible Interpretation Consistent with Published Data

The enhancement of oncogenic transformation in the C3H10T1/2 system by protraction of a high-LET irradiation has been widely reported. Prima facie, the results are inconsistent in that some but not all experiments have shown an enhancement. That the reported data follow a clear pattern is shown, and a model whose predictions are quantitatively consistent with these trends is discussed. The model, developed from that originally suggested by Rossi and Kellerer (1986), postulates that cells are especially sensitive to radiation during some period of their cycle. A sensitive period of about 1 h is shown to yield predictions consistent with all available data. If the suggested model is realistic and applicable to human cells in vivo, little enhancement would be expected for high-LET radiations such as from radon daughters or HZE cosmic rays, though an effect might be expected from trapped protons on astronauts in earth orbit. For fission neutrons a time-dependent factor of N = 2 in the formula for dose equivalent (H = DQN) might be appropriate for very low dose rates, if a quality factor Q = 10 were applied. If Q was taken as 20, then a value of N = 1 would probably be adequate.

Lack of inverse dose-rate effect on fission neutron induced transformation of C3H/10T1/2 cells.

Exponential and density-inhibited cultures of C3H/10T1/2 cells were exposed to a single dose of 0.3 Gy of fission neutrons delivered at rates ranging from 0.005 to 0.1 Gy/min. No discernible effect upon cell survival or transformation was observed by a lowering of the fission neutron dose rate in either exponential or plateau cultures. At the level of 2.3 x 10(-4) transformants per surviving cell, the RBE for neoplastic transformation was three at acute dose rates and ten at the lowest dose rate studied (0.005 Gy/min for neutrons and 0.01 Gy/min for X-rays).

Peroxidation of the Dried Thin Film of Lipid by High-Energy Alpha Particles from a Cyclotron

High-energy alpha particles produced a dose-dependent linear increase in different lipid peroxidation products (e.g., malondialdehyde (MDA), conjugated dienes, and hydroperoxides) in the dried thin film state. An inverse dose-rate effect was observed when the dose rate was varied by changing either the alpha-particle fluence rate or the alpha-particle energy. The antioxidants alpha-tocopherol and butylated hydroxytoluene (BHT) suppressed the alpha-particle-induced lipid peroxidation in the dried thin film state, and in this respect alpha-tocopherol was found superior to BHT. It was found that alpha-tocopherol was equally efficient in inhibiting lipid peroxidations by alpha particles and ultraviolet light.

Survival of cultured human cells exposed to californium 252Cf radiation at low dose rates.

Human T-1 cells were used to determine the rbe of low dose rate 252Cf (n + gamma) radiation, compared to low dose rate gamma radiation. The T-1 cells were irradiated hypoxically at room temperature, and the dose rates were as follows: a) 252Cf (n + gamma), 0.045, 0.090, and 0.270 Gy/hour; and b) 137Cs gamma radiation, 0.117, 0.246, and 0.765 Gy/hour. The RBE was obtained as the ratio of the initial slope of the 137Cs survival curves (approximately the same for all three dose rates), and the initial slope of the 252Cf survival curves (same for all three dose rates). The RBE was 5.0 +/- 1.0 for all components of the 252Cf radiation and 7.1 +/- 1.7 for the neutron components. As the dose increased, an inverse dose rate effect (more sensitive at lower dose rates) for the 137Cs survival curves was observed.

Lipid peroxidation by ultraviolet light and high energy alpha particles from a cyclotron.

High energy alpha-particles (approximately 16 MeV) and 254 nm ultraviolet light produced dose dependent linear increase of lipid hydroperoxides in the dried thin film state. For both types of radiation, an inverse dose-rate effect, i.e., a protracted radiation dose was more effective than a shorter, more intense one of larger size, was observed. Ultraviolet light (254 nm) produced higher yields of hydroperoxides in the aqueous liposomal suspension of lipid than in its dried thin film state.

Dose-rate effects on lymphocyte survival.

Lymphocytes isolated from bovine blood were irradiated at doses of 0.5, 1.0 and 1.5 Gy with dose-rates of 0.361 0.150, 0.062, and 0.006 Gy per min. The amount of trypan blue negative cells were counted directly after radiation and eight hours after the onset of the radiation, and compared with control cells. A considerable decrease of cells was found especially at the lowest dose-rate. At this low dose-rate, radiation induced cell loss already occurred during the irradiation period. These experiments suggest that the observed inverse dose-rate effects on lympocyte survival are caused by radiation induced damage to the plasma membrane of the cell. This phenomenon is especially pronounced at the lower range of dose-rates and is interpreted as a result of slowly progressing chain reactions occurring in the membranes, initiated by ionizing radiation.