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RBE FOR NORMAL TISSUES AT LOW DOSES AND LOW DOSES FRACTION IN NORMAL AND POTENTIALLY SENSITIVE POPULATIONS, WITH EMPHASTS ON PARENCHYMAL AND VASCULAR DAMAGE IN LATE AND

Objective

THE PROGRAMME WILL BE CONCERNED WITH INVESTIGATING THE RELATIONSHIP BETWEEN TISSUE PARENCHYMA AND VASCULAR ELEMENTS IN THE DEVELOPMENT OF LATE AND CHRONIC RADIATION DAMAGE FOLLOWING IRRADIATION WITH X-RAYS OR NEUTRONS. DIFFERENT ANIMAL STRAINS WILL BE USED WITH DIFFERING SENSITIVITY TO SEE IF THE RELATIONSHIP BETWEEN EARLY, LATE AND CHRONIC RADIATION DAMAGE ARE AFFECTED EQUALLY OR DIFFERENTIALLY. LOW DOSES OF FRACTIONATED RADIATIONS WILL BE INVESTIGATED USING THE TOPPING UP TECHNIQUE TO ESTABLISH WHETHER THERE IS A THRESHOLD DOSE/FRACTION BELOW WHICH NO FURTHER SPARING OF DAMAGE OCCURS BY INCREASING FRACTIONATION OF DOSE.
Relative biological effectiveness (RBE) measurements were made at low doses or fraction in the cervical cord with X-rays and neutrons of high and intermediate energy. Measurements were made of vascular permeability and these were used as markers of injury to the blood brain barrier. Also, attempts were made to reduce radiation injury to the central neurons systems (CNS) by the use of vasoactive drugs given postirradiation.

It was clear from the fractionation studies that the RBE for damage to the CNS at low doses per fraction was higher than for most other tissues. It was observed that the very high energy beam was also slightly less effective than at more moderate energies. These results emphasize the need to take great care when using fast neutrons to treat regions including the CNS.

Verapamyl, a calcium channel blocker, was used in an attempt to reduce permeability and hence oedema. It was not effective, possibly because it is the sodium channels which are opened by radiation injury and the damage is therefore unaffected by calcium channel blockers.

Dipyridamole, a muscle relaxant, was used to increase blood flow and thus reduce vessel blockage and transient ischaemia. It also reduces the thrombotic activity of the blood. This drug was effective in reducing the level of radiation damage.

Reperfusion injury is damage resulting from the production of superoxide radicals when previously ischaemic tissue is exposed to oxygen. Iron is a catalyst to the reaction. Desferrioxamine, a chelating agent, was given in combination with a low iron diet in order to decrease reperfusion injury. The low iron diet was necessary to reduce the replacement of free iron in tissue which was removed by the desferrioxamine. This drug combination was also effective. The result is also important in that it provides evidence that reperfusion injury may play a role in the development of radiation damage.

These studies demonstrate that it is possible to interfere with a ameliora te radiation damage by appropriate treatments postirradiation. The consequences for both radiation therapy and radiation protection could be considerable.
IN SPINAL CORD THE FIRST PHASE OF LATE DAMAGE PRODUCING SYMPTOMS OF ATAXIA AND PARALYSIS AT 3-7 MONTHS POST-IRRADIATION IS CURRENTLY ATTRIBUTED TO DAMAGE TO GLIAL ELEMENTS, THE OLIGODENDROCYTES, WHICH ARE CONCERNED WITH MYELINATION IN THE CNS. IT HAS BEEN SUGGESTED THAT FOCI OF DEMYLINATION DEVELOP INTO NECROSIS OF WHITE MATTER. HOWEVER THERE IS NO KNOWN NEURO-PATHOLOGICAL PATHWAY LEADING FROM DEMYLINATION TO NECROSIS. NECROSIS ATTRIBUTABLE TO NERVE DAMAGE ONLY FOLLOWS WALLERIAN DEGENERATION. IT HAS BEEN SUGGESTED THAT A TRANSIENT DEMYLINATION OCCURS AND INDEPENDENTLY SCATTERED WALLERIAN-TYPE DEGENERATION OF AXONS FROM ABOUT 2 WEEKS POST-IRRADIATION. IF AT THE SAME TIME THERE IS A TRANSIENT LOOSENING OF THE BLOOD BRAIN BARRIER DUE TO RELAXATION OF THE TIGHT JUNCTION BETWEEN CAPILLARY ENDOTHELIAL CELLS THIS MAY BE A SIGNIFICANT EVENT IN THE DEVELOPMENT OF NECROSIS. GLIAL ELEMENTS EG. ASTEROCYTES MAY BE INVOLVED IN THIS RELAXATION OF THE BLOOD BRAIN BARRIER.
IT IS PROPOSED TO INVESTIGATE THE DISRUPTION OF THE BLOOD BRAIN BARRIER USING DIFFERENT SIZED MOLECULES EG. ALPHA AMINO ISOBUTERIC ACID, WHICH IS ACTIVELY TRANSPORTED ACROSS THE BARRIER, AND BY THE PASSIVE LEAKAGE OF HORSE-RADISH PEROXIDASE WHICH CAN BE DETECTED HISTOCHEMICALLY. IF LEAKAGE CAN BE DETECTED IT MAY BE POSSIBLE TO DEVELOP TECHNIQUES USING RADIOLABELLED TRACERS (EG. INDIUM LABELLED EDTA) WHICH CAN BE DETECTED NON-INVASIVELY WITH A GAMMA CAMERA OR OTHERS WITH A POSITRON SCANNER. IT MAY ALSO BE POSSIBLE TO DETECT FLUORINE ALPHA AMINOBUTYRIC ACID LABELLED OR ATP CHANGES ASSOCIATED WITH ISCHEMIA WITH NMR SPECTOGRAPHY WHEN THIS BECOMES AVAILABLE.
THE DEVELOPMENT OF SYMPTOMS ARE DIFFERENT IN MOUSE AND RAT AND ANY DIFFERENCES IN VASCULAR LEAKAGE OR HISTOPATHOLOGY IN THE TWO SPECIES MAY GIVE SOME INSIGHT INTO MECHANISMS OF DAMAGE.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Medical Research Council (MRC)
Address
20 Park Crescent
W1N 4AL London
United Kingdom