Objective
STUDIES ON MYELOID LEUKAEMIA AND OSTEOSARCOMA INDUCED IN MICE BY RA-224.
The aims of the research were:
to confirm that myeloid leukaemia is induced by single injected amounts of radium 224 which are less than optimum for inducing osteosarcoma;
to determine whether, in this range of administered amounts of radium 224, the yield of myeloid leukaemia is greater than that of osteosarcoma;
to determine whether the yield of myeloid leukaemia is increased by injecting the same overall amounts of radium 224 in multiple aliquots over a period of time. The experimental data suggest that more myeloid leukaemia than osteosarcoma is induced in the range of administered amounts of radium 224 between 70 and 600 Bqg{-1}. If these findings are accepted as relevant to humans then persons exposed to amounts of alpha particle emitter less than optimum for inducing osteosarcoma may be at risk instead from myeloid leukaemia. There are several features of the myeloid leukaemia seen in the mice which are similar to those seen in human acute myeloid leukaemia and recent (unpublished) observations have shown that of the 7 possible subtypes of myeloid leukaemia seen in humans (FAB classification) 5 have been provisionally identified by blood cell morphology in the mice used in the present experiments. Finally, however, it is only in the elucidation of the mechanisms of leukaemogenesis in both mice and humans that the nature of the this response to radiation can be fully identified and true value of the mouse model understood. Epidemiological evidence from patients treated with radium 224 in the German Federal Republic before 1950 showed conclusively that osteosarcoma was the major late effect (Mays et al 1986). In these studies, although there were 53 cases of osteosarcoma (compared with 0.2 cases expected) there was a stated incidence of only 0 - 3 excess cases of myeloid leukaemia attributable to radium. This evidence appears to show therefore that the sensitivity of humans to alpha particle induced osteosarcoma is at least an order of magnitude greater than is their sensitivity of myeloid leukaemia. The experimental showed, however, that in mice there is a region of exposure to radium 224 below that which caused a maximum yield of osteosarcoma. If these results can be used as a model for man then it might be expected that there is a similar region in human exposure to radium 224 than in the earlier study the 3 bone tumours which have been diagnosed in the exposed population (fibrosarcoma, reticulum cell sarcoma of the bone marrow and generalised plasmocytoma, Wick et al 1986) contrast with the types of bone tumours (mostly osteosarcomas) which were diagnosed in the population exposed to larger amounts of radium 224 (Mays et al 1986). Leukaemia has also been diagnosed in the patients given the smaller amounts of radium 224 although their induction by radiation has not so far been claimed. The ultimate findings of these studies will have an important bearing on the question of human sensitivity to the induction of leukaemia by bone seeking alpha particle emitting radionuclides.
Cytogenetic studies have revealed that the chromosome 2 rearrangements and deletions that characterise radiation induced murine acute myeloid leukaemia (AML) may have their origins in directly induced chromosomal damage in multipotential haemopoietic cells. Molecular studies have so far failed to unambiguously identify specific chromosome2 encoded genes involved with chromosome2 rearrangement but Il-1beta appears to be close to a chromosome2 translocation junction in one AML and may be deregulated as a consequence of a flanking sequence rearrangement. Cytogenetic analysis has been used to show that alpha particles are inefficient at inducing stable chromosomal change in multipotential haemopoietic cells and it is suggested that these cells are hypersensitive to the lethal effects of alpha irradiation. This may account for the weakly leukaemogenic effects of bone seeking alpha emitting radionuclides. The cytogenetic studies outlined here point towards multisite fragility of murine chromosome2 in haemopoietic cells to X-irradiation. The molecular basis of this remains unexplained but some chromosome2 breakpoint clusters in AMLs and irradiated haemopoietic cells cytogenetically correspond to constitutive chromosomal fragile sites recently identified in the mouse (Djaladi M et al Hum Genet 77, 157, 1987).
Current cytogenetic studies with X-irradiated CBA/H embryo fibroblast cultures suggest that perhaps one copy of chromosome2 in this mouse strain is uniquely sensitive to radiation induced breakage and that this unexpected feature is determined by germ line deoxyribonucleic acid (DNA) sequences encoding regions of instability possibly imprinted during gametogenesis. If correct, this hypothesis predicts that the high frequency of chromosome2 rearrangement observed in irradiated haemopoietic cells repopulating marrow ablated recipients may not reflect any immediate phenotypic effect of chromosome rearrangement (ie through gene activation and selective clonal advantage) but is simply a consequence of the extremely high post irradiation frequency of these events in certain somatic tissues of this mouse strain. This explanation would account for the high sensitivity of a mouse strain. This explanation would account for the high sensitivity of a mouse strain, showing a low spontaneous incidence, to radiation myeloid leukaemogenesis. The hypothesis may also imply the requirement for a second genetic event, probably on the other chromosome2 homologue of a chromosome2 rearranged/deleted haemopoietic clone, in order to fully initiate leukaemogenesis.
The potential contamination of the environment by the nuclear power industry and the heightened public awareness of the threat of radiation, maintains the need for the experimental investigation of the effects of alpha-particle emitters. Leukaemia is perceived to be the greatest threat, yet the risk of its induction from alpha-particle emitters is not yet convincing; this study is concerned principally with the investigation of this risk in mice. The work is divided into 2 areas:
to investigate of the ratio of induced myeloid leukaemia to that of osteosarcoma as a result of single injections of different amounts of radium-224 into adult male CBA/H mice;
to study the late effects arising from the administration of radium-224 to adult and 4 week old male CBA/H mice protracted over 8 weeks; and the continuous administration of radium-224 from paratibially injected thorium-228.
The male CBA/H mice (79-89 [average 84] day old) used in the long term study of the effect of single intraperitoneal injections of radium-224 (or of diluting solution only) are now dead. The results so far show an overall 6 fold greater incidence of myeloid leukaemia than of osteosarcoma, in the range 69 to 550 Bq/g radium-224 administered and that the yield of myeloid leukaemia increases with the amount of radium-224 injected. Histopathological analyses, however, are not yet complete and the final ratio of myeloid leukaemia to osteosarcoma may still change.
An experiment was carried out in which 16 intraperitoneal injections of radium-224 (or of diluting solution) were made over an 8 week period into 12 week old mice. A difference between the yield of myeloid leukaemia in the group given 128 Bq/g radium-224 and an interpolated value from the single injection experiment was apparent however this has been shown to be statistically insignificant.
The prohibitively timeconsuming nature of multiple injections of large numbers of mice over long periods prompted the investigation of paratibi al injection of thorium-228 as a source of radium-224. This method inovlves the injection of thorium-228 in a form which allows the bulk of the parent thorium to remain at the site of injection (near to the tibiofibula in the left leg) while the radioactive daughters are distributed by the circulation. Effectively therefore, since thorium-228 has a very much longer half life than any of its daughters and since radium-224 is the first daughter, a paratibial injection of thorium-228 is equivalent to a continous contamination by radium-224. In addition to eliminating the labour intensive need for repeated injection this method has the obvious advantage of simulating the exposure conditions which might result from an environment contaminated by alpha-particle emitters. Preliminary measurements have confirmed the tissue distribution of radium-224 already observed in NMRI mice. These measurements have also shown that lead-212 accumulates continuously in blood, tentatively confirming that radon-220 was being lost from bone.
1. RATIOS OF YIELDS OF MYELOID LEUKAEMIA AND OSTEOSARCOMA INDUCED IN MICE BY RA-224.
2. THE ROLE OF ONCOGENE ACTIVATION IN RA-224 INDUCED MYELOID LEUKAEMIA.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- natural sciences chemical sciences inorganic chemistry alkaline earth metals
- medical and health sciences clinical medicine oncology leukemia
- medical and health sciences clinical medicine embryology
- natural sciences chemical sciences nuclear chemistry radiation chemistry
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