The reduction of radiation damage to the spinal cord by post-irradiation administration of vasoactive drugs.

Radiation induced white matter necrosis in the rat spinal cord is preceded by changes in permeability of the blood brain-barrier, reduced blood flow, and infarction so that the necrosis is an ischemic necrosis. Attempts have been made to modify this developing pathology by the administration of drugs post-irradiation but just prior to the changes in vascular permeability. Verapamyl, a calcium channel blocker, had no effect on the development of ataxia. Dipyridamole, a drug which increases blood flow and reduces thrombosis, delayed and reduced the onset of ataxia. A low iron diet and desferrioxamine which reduces reperfusion injury also delayed and reduced ataxia. These results support the thesis that vascular changes are an important pathway in the development of radiation necrosis and that reperfusion injury is an important factor in the development and exacerbation of radiation damage to the spinal cord.

Changes in relative biological effectiveness with depth of the Clatterbridge neutron therapy beam.

We have measured the biological equivalence of the Clatterbridge neutron therapy beam [p(62)-Be] and the Hammersmith neutron therapy beam [d(16)-Be] using the mouse intestinal crypt assay. The ratio (NDR) of Clatterbridge neutron (n + gamma) dose relative to Hammersmith neutron dose (n + gamma) was found to be 1.2-1.13 over a dose/fraction range of 1.8-9 Gy at 2 cm deep in a Perspex phantom. It is shown that the effectiveness of the Clatterbridge beam was reduced with penetration into the phantom because of hardening of the beam to a maximum reduction of 11% at 12 cm deep in the phantom. The hardening of the beam with depth of penetration will need to be taken into account by clinicians in assessing the tumour dose and tissue tolerance. Relative biological effectiveness values for the Clatterbridge and Hammersmith neutron beams were also measured. All neutron doses for both Hammersmith and Clatterbridge beams are total doses (n + gamma) which comply with the European protocol for neutron dosimetry and include the gamma-ray component of dose.

DNA quaternary structure in the radiation sensitivity of human lymphocytes--a proposed role of copper.

On challenging with 2M NaCl, the nuclei of human lymphocytes yield an aggregate of DNA-protein material. The density of the material is less when isolated from irradiated cells than when isolated from unirradiated cells. The density of this material, designated histone-free-DNA (HF-DNA), from irradiated cells returns to that from unirradiated cells if the irradiated cells are allowed time at 37 degrees C in nutrient conditions. Lymphocyte HF-DNA from patients who have exhibited hypersensitivity to radiotherapy exhibit slower repair characteristics than lymphocyte HF-DNA from the average normal subjects. Neutrons are more effective than X-rays in producing density changes. Misonidazole and the ADPRT inhibitor 3-AAB substantially inhibit return to unirradiated densities. The oer for the initial effect is between 2 and 3. These properties of this DNA material from human lymphocytes suggest that alterations in the configuration of such material by the loss and re-establishment of relatively weak cellular bonds are closely related to the well-known changes observed in classical cell survival experiments. Where the proliferation of human lymphocytes has been observed by concanavalin A stimulation, oer, RBE and chemical modification has been of the same order as the measured density changes. Additionally, we have found that the density of HF-DNA is heavily dependent upon Cu content. This has led us to propose that cell killing or malfunction at the nuclear level caused by ionizing radiation is caused by the conversion CuII----CuI and also by specific .OH attack on DNA or proteins at a Cu site.(ABSTRACT TRUNCATED AT 250 WORDS)

Sensitivity to X-irradiation of peripheral blood lymphocytes from ageing donors.

The proliferation of human blood lymphocytes from ageing donors, responding to concanavalin A, showed greater sensitivity to inhibition by X-rays than similar cells from younger donors. This increased sensitivity was associated with deficiency in repair of X-ray-induced damage to nuclear material, as measured by density in sucrose gradients, and with increased incidence of chromosomal damage following exposure of freshly isolated lymphocytes. There was also an increased frequency of spontaneous chromosomal aberrations in ageing subjects whose lymphocytes were deficient in repair of DNA damage.

Radiation injury in mouse lung: dependence on oxygen levels in the inspired gas.

The relationship between radiosensitivity and the partial pressure of oxygen (PO2) in the inspired gas has been established for radiation pneumonitis as a measure of lung damage following irradiation of the mouse thorax. The radiosensitivity at low PO2 (0-1 per cent) fitted the linear transformation of the Alper, Howard-Flanders relationship giving a K value for lung tissue of 1.35 per cent oxygen with an oxygen enhancement ratio, m, of 2.13. The radiosensitivity at higher PO2 (5-21 per cent) did not fit the Alper, Howard-Flanders relationship probably because the PO2 of the inspired gas was greater than the PO2 in the alveolus. At the low PO2 levels in the inspired gas, back diffusion of oxygen from blood into the alveolus may lead to errors in the estimated value of K. If the low value of m is due to this 'contaminating' oxygen from blood then by taking a higher value for m, the amount of contaminating oxygen can be calculated (0.23 per cent) and a 'true' value for K(1.1 per cent) determined. Other uncertainties in this estimate of K due to the radiolytic consumption of oxygen and possible inadequacies in equilibration are discussed. Allowing for the uncertainties, it is concluded that the K value for lung damage lies towards the upper end of the range of K values measured for cells in vitro.

The effect of neutron dose rate on jejunal crypt survival.

The effect of dose rate of fast neutrons over a range from 0.02 Gy/min to 22.5 Gy/min on the survival of mouse jejunal crypts was investigated. A small but significant decrease in sensitivity with decrease in dose rate was observed. A 10-fold decrease in dose rate gave a decrease in effectiveness equivalent to 0.39 Gy. The sensitivity to changes in neutron dose rate is much smaller than the sensitivity to changes in dose rate of photons.

Differences in repair in heterogeneous cell populations in vivo and in vitro following high LET irradiation (neutrons).

The shape of cell survival curves following X-irradiation when the X-rays were given immediately after neutron irradiation has been examined in two cell lines in vitro (Ehrlich ascites and V79) and in the stem cells of the mouse jejunum. The changes in the shape of the X-ray survival curve following neutron irradiation are different in all the cell systems examined. Some of the changes observed may be associated with a change in the cell profile following neutron irradiation due to the more even cell age killing pattern of neutrons through the cell cycle compared with X-rays. It is unlikely that this can account for all changes in shape observed and it is postulated that some cells following neutron irradiation are more sensitive to X-rays than the unirradiated population or than X-irradiated cells at the same level of survival. This increased sensitivity may be associated with a non-reversible sublethal damage or a saturation of the repair potential caused largely by the alpha or heavy recoil (HR) particles produced by the neutrons in the cell nucleus. The damage is observed when the probability of alpha or HR particles being produced within the cell nucleus, without killing the cell, is high.

RBE for lung and cord.

The sparing effect of fractionation of neutron dose is very small for late damage in tissues. This is seen in the almost flat isoeffect curve for damage to skin, CNS and to lung. This means that differences in the RBE curves for these tissues are determined by differences in the slopes of the photon isoeffect curves. The relevant slopes of the photon isoeffect curves giving the exponent of N in the Ellis formula are 0.24 for subcutaneous tissue, 0.27 for lung damage and 0.38-0.45 for damage to spinal cord, while the exponent for N for neutrons for these tissues is 0.04 for subcutaneous tissues and zero for lung and spinal cord. The slopes of the RBE curves for lung and cord or for skin and cord when RBE is plotted against dose/fraction of photons are significantly different, and the RBE at a gamma ray dose/fraction normally used in therapy of about 2 Gy, is significantly higher for spinal cord than for lung or skin. The sparing of damage by extending overall treatment time for both lung and CNS is small for X or gamma-irradiation. For neutron irradiation the sparing is similar to that with photons for the CNS but is much less with neutrons than with photons for the lung. This is because different mechanisms are responsible for this type of sparing of damage in the two tissues. In lung slow, repair is involved while in the spinal cord, the sparing is related to the slow cell proliferation.

Residual injury in the spinal cord after treatment with X rays or neutrons.

Residual injury in the spinal cord 100 days after X rays or neutrons was measured by the reduction in dose of a second radiation required to produce nerve damage assessed by the development of ataxia within the first post-irradiation year. Between 5-10% residual damage was observed after X-ray doses of 25% or 50% of the single X-ray dose which produced ataxia in 50% of animals (ED50), but 30% residual injury was observed if the X-ray dose was 75% of the ED50 dose. Neutron doses of 25% and 50% of the ED50 neutron dose gave the same level of residual injury as observed after equivalent X-ray doses, indicating that for this type of damage the shedding of residual damage was similar after X rays or neutrons. More residual damage is observed after a dose of X rays for vascular related damage than for damage associated with glial cell loss. However, if residual damage is expressed in terms of the relevant vascular or glial cell damage caused by the priming dose the same relationship between primary damage and residual damage is seen for both glial and vascular related damage.

Effects of x-irradiation on axonal sprouting induced by botulinum toxin.

The effect of X-irradiation on axonal sprouting of motor nerves induced by botulinum toxin was examined. Muscles of one leg in the mouse were X-irradiated (15 Gy) prior to the injection of a locally paralysing dose of botulinum toxin. It was found that axonal sprouting occurred as expected, but the sprouts remained unmyelinated and many degenerated. Fewer new end-plates were formed, muscles remained more severely atrophied and supersensitive to acetylcholine and recovery of neuromuscular transmission was greatly delayed when compared with the effects of botulinum toxin alone. The experiments show that X-irradiation did not prevent sprouting but, probably by impairing Schwann cell proliferation, altered axon-Schwann cell relationships and prevented the maturation of newly-formed axons and the differentiation of new end-plates.

Histology of the irradiated rat brain in the first post-irradiation year.

The histology of the brains of rats killed were studied, following various doses of 250 kV X rays. The majority of rats which were killed before 200 days showed no damage to the mid-brain and cerebral hemispheres. However, the trigeminal and facial nerves exhibited necrosis, the origin of which was probably in the central nervous tissue of the transitional region between central and peripheral nerve systems. The result of these lesions was atrophy of the masticatory muscles and a consequent difficulty in feeding. Rats surviving beyond 200 days post-irradiation exhibited focal necrosis within central white matter regions which resembled, both in form and location, those described in previous reports for rats.

Turnover of proliferative cells in the spinal cord after X irradiation and its relation to time-dependent repair of radiation damage.

The changes in labelling index of neuroglial cells of the rat cervical cord following 20 Gy X rays are compared with the timing and pattern of the repair of radiation damage in the spinal cord. The start of time-dependent repair coincides with the release of the proliferative neuroglia from a block at the G1/S border. The evidence suggests that the time-dependent repair reflects the normal unstimulated proliferation of the surviving neuroglial cells and that homeostatically stimulated recruitment to the proliferative neuroglia does not occur until the period just before the development of paralysis. A normal cell-cycle time of about one month for the spinal cord neuroglia is indicated from the observed pattern of labelling.