Current topics in radiation research quarterly最新文献

In its decay, iodine-125 emits cascades of Auger electrons with subcellular ranges and leaves a highly charged tellurium-125 product. When iodine-125 is incorporated into DNA as the thymidine analog 125I-UdR, the localized deposition of such energy has been shown to be extremely radiotoxic. This report presents the results of quantitative investigations into the therapeutic efficacy of 125I-UdR in an early ascites murine tumour model. An ovarian embryonal cell carcinoma has been maintained by serial intraperitoneal transplantation. Challenge doses of 10(4)-10(6) cells were used. Four divided doses of 125I-UdR were administered starting 24 h after tumour cell inoculation; the interval between doses was 4 or 12 h. Therapeutic efficacy was demonstrated by prolonged median and increased absolute survivals of treated animals. Divided doses were more effective than single doses, and antineoplastic activity was related to fractionation. The degree of cell killing with a given fractionation scheme was constant over the range of 10(4)-10(6) cells, and total doses of 50-100 muCi resulted in a 2-3 log killing of tumour cells (1-0.1% cell survival). Therapy with 125I-UdR affords a promising new approach to the treatment of cancer. The therapeutic potential of iodine-125 and other radionuclides whose decay results in a highly localized deposition of energy merits further investigation.

Many hundreds of clearance curves for plasma and urine after a single injection of tracer are well fitted by y = sigmari = Ai exp(-Bit), r = 2 or 3, based on models with homogeneous compartments. Reanalyzing such sums as in a plot of log y versus log t shows that many of the original curves would fit y = At-alpha or At-alpha exp(-betat) over wide ranges of time and specific acitivity. Results of such reanalyses for a complete published series for serum albumin 131I are given, and an outline of those for various compounds in the human body labeled by 3H. For radiocalcium two such power laws can be fitted in one curve, with a transition between about 1 and 3 days, so that much of the log y versus log t plot consists of two straight lines. These lines are used for starting a numerical analysis that splits the curve into 2 non-linear components, plus a third one that is neglibible after 5 min from injection. An outline of the iteration method is given. The components are interpreted physiologically and used to predict total bone activities by (de)convolution, and these are compared with observed ankle activities and with excretion rates. The bone accretion rate is obtained mainly from the middle component and comes to 2 to 3 g Ca/day, while return of 47Ca from bone to plasma begins at about 1/2 day. These results seem imcompatible with any based on compartments. The concept of biological half-life then needs to be reconsidered.

A research programme on the transfer of tritium in the food chain has been in progress for several years on the experimental farm of the Nuclear Energy Research Center at Mol. The studies reported here are related to the distribution of tritium in the organs of farm animals contaminated in various ways. Two young male calves ingested tritiated milk; the daily intake of 3H-organic form was about 15 muCi for each calf and the total activity ingested until the sacrifice was 482 muCi. Three male pigs from the same litter and about 7 weeks old were used for each experiment on the administration of tritium under different forms: (a) single intraperitoneal injection of 39.3 mCi HTO (P2, P3, P4). (b) daily ingestion of 28.4 muCi HTO. The total activity ingested was respectively 569 muCi (P5) and 766.8 muCi (P6). (c) ingestion of tritiated potatoes. The total activity ingested was respectively 21 muCi (P8), 40.3 muCi (P9) and 48.1 muCi (P10). (d) ingestion of tritiated milk powder. The total activity ingested was respectively 60.6 muCi (P13), 110.4 muCi (P11) and 154.5 muCi (P12). After slaughtering of each animal various organs were removed and analyzed for the 3H content in the tissue water and in the organic matter. We could verify that the chemical form of 3H present in the food is of great importance for the incorporation of 3H in the organic matter of the animal organs. The total incorporation increases by a factor 5.6 when 3H is ingested as tritiated milkpowder by pigs as compared to HTO and with a factor 15 for calves. When tritiated potatoes were ingested by pigs a factor 15.6 was found. The transfer of 3H from HTO and milk feed ingested in the organic fraction of organs is lower for pig than for calf. When we consider the 3H in the tissue water of organs the specific activity (SA) is a little lower than the SA of ingested HTO and after ingestion of tritiated milk feed the activity is very low and no difference due to the species is found. After fractionation of liver and spleen tissue following the technique of Schmidt--Thannhauser radioactivity was found in all liver and spleen constituent lipids--RNA--DNA and proteins, but after isolation and purification of DNA following the original methods, we have not been able to demonstrate that tritium is really incorporated into DNA molecules of a non-dividing organ such as the liver nor of an actively dividing organ such as the spleen.

The relative toxicity of DNA precursors labeled with iodine-125, iodine-131, or hydrogen-3 was studied in exponentially growing Chinese hamster cells. Per decay, iodine-125 was found to be approximately 12 times as lethal as iodine-131 and 16 times as lethal as hydrogen-3. Chromosomal aberrations induced in these cells by the three radionuclides occurred with the same relative efficacy as their lethal effects.

Since the first promising results of Nouel et al. 1972, additional positive experience has been obtained with 57Co-Bleomycin (57Co-BLM) as a tumour-localizing agent. In this preclinical study, mice with transplanted osteosarcoma and lymphosarcoma were used and rats with transplanted rhabdomyosarcoma. 57CoCl2 served as a control substance. 57Co-BLM had concentrated in the tumours with a factor 2 to 10 as compared to the (normal) liver of the animals. No preferential concentration in the tumours was found when 57CoCl2 was used. The highest specific activity of 57Co-BLM (cpm/mg protein) was found in a fraction containing mitochondria and lysosomes. Evidence for a lysosomal localization of this diagnostic compound was obtained from experiments in which the mitochondrial-lysosomal fraction was treated with hypertonic media of different osmolarities. Conditions could be found in which many lysosomes burst while almost all mitochondrial were intact. From these experiments it appeared that the radioactivity in the particles obtained from animals injected wtih 57Co-BLM was released very rapidly. It is concluded that 57Co-BLM is preferentially localized in the heavy lysosomes sedimenting together with most of the mitochondria of the cell and that these structures are more fragile than the light lysosomes.

Wild-type M. radiodurans and two radiosensitive mutants were used to study the lethal effects of 125I disintegrations in their DNA. The relative sensitivities of these three strains to inactivation by gamma-radiation were reflected in their relative sensitivities to inactivation by 125I decay. The number of double-strand (ds) breaks in the DNA appeared to be similar at levels of gamma-radiation and of 125I decay that reduced survival to 10%. All three strains of M. radiodurans rapidly repaired ds breaks produced in their DNA by either gamma-radiation or 125I disintegrations. If one ds break per is a lethal event [Kirsch et al., 1975], cells of the three strains tested would die only when they had left unrepaired one ds break out of an initial 45,600 or 1800 ds breaks per single cell.

Biological effects of 125I incorporated into DNA exceed those to be expected from the absorbed radiation dose by a factor 3--30. The reason for this discrepancy suggests special mechanisms introduced by 125I transmutation, decays by K-capture leading to the emission of an average of 6 low energy electrons including Auger electrons and to a highly positively charged daughter nuclide. The effect of 125I decay on DNA strand breakage and subsequent repair was studied. Human kidney cells T in the deep frozen state (-196 degrees C) were exposed to incorporated 125I and 60Co gamma-rays. The number of DNA single strand breaks (ssb) was determined by DNA centrifugation in alkaline sucrose gradients. DNA repair was studied by incubating the cells after thawing at 37 degrees C. For 125I decay in frozen cells which were kept with or without dimethyl-sulfoxide, 4 and 6 ssb were measured per decay. The gamma-rays produced 1ssb per 26 eV absorbed energy. Most of this damage was repaired 30 to 40 min after onset of incubation. No repair of the damage caused by 125I was observed. The high efficiency of 125I decays for the production of unreparable ssb provides evidence for the high radiotoxicity of this isotope. The observed lack of repair may in part be due to the high numbers of at least 2,000 125I decays per cell nucleus necessary for the assay system. Damage from many 125I decays may interfere with enzymatic repair processes.

Hooded inbred rats were given subcutaneously HTO doses ranging from 1.8 muCi/g b.w. to 115 muCi/g b.w. Samples of liver, lung, kidney, skin muscle, small and large intestine were taken at 1, 3, and 5 days intervals within 21 days of the experiment. The concentrations of tritium in free water and bound in particular tissues have been determined, and the biological half-lifes (Tb) of tritium were calculated by means of least squares. The biological half-life of free-water tritium varied from 3.6 days in kidney to 4.8 days in muscle for the control group being slightly lower in the groups with higher HTO doses. The retention of tissue-bound tritium varied in each group of animals. Tb values varied from 10.3 days in the large intestine to 85.0 days in the muscle of the control group and were significantly lower at higher HTO doses. This result is opposite to the effect observed after external X-ray irradiation for the same radiation dose level.

The long term somatic and genetic effects of chronic tritium (3H) ingestion have been measured in mice. Second generation animals, who with their parents were maintained on drinking water containing 3 muCi/ml of HTO, have been bred and the number of dominant lethal mutations measured. The increase in dominant lethal mutations in treated animals as compared to tap water controls is significant at the 1% level. The stem cell content of the bone marrow has been measured throughout the lifetime of the animals. A slight reduction in colony forming units in the bone marrow of treated animals is evident beginning after approximately 12 weeks, increasing in severity throughout the lifetime of the animals. The distribution of tritium in tissue water protein fractions was determined, and the relative contribution to tissue dose calculated. The differential incorporation into protein fractions was not found to be significant.

In view of the enhanced biological damage caused by the "Auger nuclide" iodine-125, we have carried out quantitative ESR-studies of the radical formation in polycrystalline 5-iododoeoxyuridine (IUdR) resulting from the following internal or external radiation sources: (1) Decay of 3H, 125I or 131I in labeled IUdR; (2) Lanthanum K-photons corresponding to the K-edge of iodine; (3) 60Co gamma-rays. The results clearly indicate that inner shell ionization with its accompanying Auger effect as caused by the lanthanum K X-ray produces about 30% more free radicals per unit dose absorbed than 60Co gamma-rays, when considering the long-lived secondary radicals. Similarly, the concentration of free radicals is by about 30% higher in 125I- than in 131I-labeled IUdR at comparable doses. In the case of 3H-labeled IUdR the dose curve is almost identical with that observed for 125I-labeled IUdR. The results are discussed in terms of a localized radiation damage from low energy electrons.