The DNA Content of the Small Intestine as a Quantitative Measure of Damage and Recovery after Whole Body Irradiation

Summary

(1) The total amount of deoxyribonucleic acid (DNA) in the small intestine was used as a measure of cell population in order to follow the course of radiation damage in mice and rats. Changes in total DNA-P were proportionately larger and intrinsically less variable than changes in fresh weight of the intestine.

(2) In unirradiated control mice intestinal DNA-P concentration was constant but intestinal weight and total intestinal DNA-P were linearly dependent on body weight.

(3) Single doses of whole body irradiation given to mice caused a fall in total intestinal DNA-P which began 12 hours later. Except after 25 000 r which had less effect than 5000 r, the larger the dose of radiation the greater the maximum depression in DNA-P and the later the time at which recovery began. The course of recovery was exponential after 1000 r but not after 750 r.

(4) In both rats and mice β-mercaptoethylamine reduced the damaging effect of a dose of radiation but did not modify the course of recovery.

(5) Chronic irradiation of mice at levels sufficient to reduce body weight slightly caused a loss in total intestinal DNA-P. The loss was probably, but not certainly, greater than that expected from the loss in body weight alone.     

Personal dosimetry of the staff during treatment of neuroendocrine tumours with a high dose of Indium-111 Octreotide.

BACKGROUND: Therapeutic doses with Indium-111 (In-111)-DTPA-Octreotide are currently used in patients with somatostatin receptor positive tumours. It may result in tumour regression in some patients and this effect is ascribed to cell and receptor specific cytotoxicity by Auger or conversion electrons. Personnel being involved in this treatment may receive high radiation doses due to the emission of 173 keV and 247 keV photons. The aim of the present study was to assess the radiation dose to the personnel at different time intervals during treatment with Indium-111 Octreotide. METHODS: Five consecutive patients suffering from a neuroendocrine tumour were included in this dosimetry study. In total, 18 treatments with Indium-111 Octreotide have been given with a mean dose of 8000 MBq every three weeks. Three dosimeters (whole body, left and right hand) and a dose rate monitor were used to register doses and dose rates during labelling, administration and in-patient follow-up and whole body scintigraphy. These procedures were performed by a pharmacist, a nuclear physician and a technologist, respectively. RESULTS: The whole body dose received during the labelling procedure was 5 microSv. The mean total exposure time during administration, whole body scintigraphy and clinical follow-up was 47 minutes revealing a mean whole body dose of 45 microSv. The mean radiation dose to the hands was 60 microSv per treatment. CONCLUSIONS: The radiation risk to staff members and technologists seems to be very low during in-patient treatments with high dose Indium-111 Octreotide. According to the safety regulations no special radiation protection measures or personal dosimetry is required.     

Mitigation of experimental radiation nephropathy by renin-equivalent doses of angiotensin converting enzyme inhibitors

Abstract

Purpose: We tested five different angiotensin converting enzyme inhibitors (ACEI) as mitigators of experimental radiation nephropathy at drug doses calibrated to the plasma renin activity (PRA). This was done to determine whether all ACEI had the same efficacy as mitigators of radiation nephropathy when used at drug doses that gave equivalent suppression of the renin angiotensin system.

Method: 10 Gy total body irradiation with bone marrow transplantation was used to cause radiation nephropathy in barrier-maintained rats. Equivalent ACEI doses were determined based on their effect to inhibit angiotensin converting enzyme (ACE) and raise the PRA in unirradiated animals.

Results: PRA-equivalent doses were found for captopril, lisinopril, enalapril, ramipril and fosinopril. These doses overlap the human doses of these drugs on a body surface area basis. All ACE inhibitors, except fosinopril, mitigated radiation nephropathy; captopril was a somewhat better mitigator than lisinopril, enalapril or ramipril.

Conclusions: Most, but not all, ACEI mitigate radiation nephropathy at doses that overlap their clinically-used doses (on a body surface area basis). Fosinopril is known to be an ineffective mitigator of radiation pneumonitis, and it also does not mitigate radiation nephropathy. These pre-clinical data are critical in planning human studies of the mitigation of normal tissue radiation injury.     

Drug combination against single drug treatment in radiation protection of the bone marrow CFU

The ability of WR-2721 to protect normal tissues against ionizing radiation is limited at its maximum protective dose owing to the toxicity of the drug per se. Previous studies had indicated that MPG (2-mercaptopropionylglycine) neutralizes to some extent the toxic effects of WR-2721 without impairing the protective efficiency. The effectiveness of two doses of WR-2721 (300 mg/kg and 150 mg/kg body weight) alone or in combination with an optimal dose (20 mg/kg body weight) of MPG, on the mouse bone marrow was studied by the exogenous spleen colony assay (CFU-s) after a single whole body exposure to 4.5 Gy of gamma radiation. Both the drugs individually increased the number of spleen colonies significantly above that of the irradiated control indicating higher stem cell survival. WR-2721 treatment gave better protection than MPG. MPG was more effective when administered within 5 min before or after irradiation than when given 30 to 25 min before irradiation. The combination of WR-2721, at either dose, with 20 mg/kg MPG gave an increase in the stem cell survival as compared to the single drug treatments and this effect was synergistic at 300 mg/kg WR-2721. MPG treatment within 5 min after irradiation produced a slightly higher CFU-s count than when the drug was injected before irradiation, though the difference was not statistically significant. It is concluded that in addition to the doses of the drug, the time of administration also could influence the effect of drug combinations.     

bFGF基因在中子辐射肠道损伤和修复中的表达和意义

目的研究肠道经中子照后的病变特点、bFGF蛋白和mRNA的表达及意义。方法采用2．5～5．5Gy中子照射230只BALB／C小鼠，于照后6和12h、1～5d、7、10、14、21和28d分批活杀，采用免疫组化和原位杂交等技术研究bFGF基因在肠组织中的表达。结果照射后隐窝细胞见凋亡与坏死，并呈剂量相关性，2．5Gy组肠黏膜见明显损伤及恢复现象。bFGF蛋白和mRNA于正常肠上皮细胞阳性，其mRNA于血管内皮和间质细胞强阳性。2．5Gy照后3d内，bFGF蛋白进行性减少，照后5～10d，绒毛上皮细胞bFGF蛋白明显增加，5d达高峰，14d恢复至正常水平。4．0Gy以上照后4d内，bFGF进行性减少。bFGF mRNA与其蛋白出现相似的变化规律，其高峰见于照后3d，10d基本恢复至正常水平。结论一定剂量的中子辐射可使肠黏膜明显损伤，并呈剂量相关性；中子照射后肠内源性bFGF基因表达参与其损伤及修复的病理过程，可能对其损伤后的修复起促进作用。     

Early Intestinal Changes Following Abdominal Radiotherapy

PURPOSE: To compare tests for intestinal function with clinical scores after abdominal irradiation. PATIENTS AND METHODS: At the Department of Radiotherapy, Erfurt, Germany, intestinal changes were studied in 91 patients receiving abdominal radiotherapy between 1992 and 1996. Conventional fractionation (1.8-2 Gy per fraction, total doses 30.6-62.5 Gy) was applied. Before and at weekly intervals during radiotherapy, the clinical response was scored according to RTOG/EORTC for the upper and lower gastrointestinal (GI) tract. Resorption tests for vitamin B(12) and D-xylose were performed before the onset and immediately after treatment. RESULTS: The clinical response displayed a well-defined dose-effect relationship with grade 1 effects in 5% and 50% of the patients at about 10 Gy and 50 Gy, respectively. For grade 2 reactions, 5%- and 50%-effective doses were 20-30 Gy and 60-80 Gy. Effects in the upper and lower GI tract were highly correlated. Changes in body weight did not show a correlation with other clinical symptoms. Changes in resorption also displayed a significant dose effect. However, no correlation was found with the clinical symptoms in the individual patient. CONCLUSION: In the present study, the clinical manifestation of intestinal side effects according to RTOG/EORTC criteria was reflected by neither the vitamin B(12) nor by the D-xylose resorption test. Hence, these tests cannot be regarded as useful for objective quantitation of intestinal radiation injury.     

rhIL-11对中子照射小鼠肠损伤的治疗作用

目的研究重组人白介素11(rhIL-11)对中子照射小鼠小肠上皮损伤及细胞周期的影响。方法采用裂变中子照射小鼠模型，观察rhIL-11对照射后小鼠小肠上皮形态、隐窝细胞坏死和细胞增生的影响，用流式细胞仪检测小鼠小肠上皮细胞周期的变化。结果rhIL-11治疗和预防给药可通过促进小肠隐窝细胞增殖使肠损伤得到迅速修复。照射后小鼠小肠上皮细胞发生明显的G2期阻滞，rhIL-11治疗可明显提高S期细胞比例。结论rhIL-11对中子照射小鼠小肠损伤具有防护作用，并能够影响细胞周期的变化。     

辐射损伤相关生物标志物的研究进展

核与辐射事故发生时,快速评估人体吸收的辐射剂量对于伤员的分类和救治极为重要。为制定有效的辐射损伤救治方案和研发抗辐射新药,辐射损伤相关生物标志物的研究引起了研究者的浓厚兴趣。通过辐射损伤相关生物标志物的变化评估辐射吸收剂量或抗辐射药物的有效性成为研究的热点。笔者围绕近年来用于评估辐射吸收剂量和抗辐射药物有效性的生物标志...     

3H-TDR labelling of osteoprogenitor cells after 226RA incorporation in mice.

The time course of 3H-TDR labelling index of osteoprogenitor cells and the doses in endosteum of lumbar vertebra and distal femoral epiphysis were autoradiographically determined in young female mice after single injections of 19.7 and 55.9 micronCi/kg body weight of 226Ra. The selected bone areas were examined in animals killed 2 hours to 28 days after the injection of nuclide. It was ascertained that changes in the relative labelling index are depending on the absorbed doses of alpha radiation. The possible relevance of these experimental findings for the explanation of the osteosarcoma induction and localization is discussed.     

Reference dosimetry and measurement quality assurance

Measurements of absorbed dose made by a reference dosimetry system, such as alanine, have been suggested for achieving quality assurance through traceability to primary standards. Such traceability can assist users of radiation worldwide in enhancing quality control in medicine, agriculture, and industry. International and national standards of absorbed dose are still needed for applications of γ-ray and electron dosimetry at high doses (e.g. radiation therapy, food irradiation and industrial radiation processing). Reference systems, such as ferrous sulfate dosimeters measured by spectrophotometry and alanine measured by electron spin resonance spectrometry are already well established. Another useful reference system for high doses is supplied as dichromate solutions measured by spectrophotometry. Reference dosimetry, particularly for electron beams, can be accomplished with thin alanine or radiochromic dye film dosimeters.     

Dose and Dose-splitting Effects of X-rays on Lung Tumour Induction in Mice

Summary

This paper reports lung-tumour induction 12 months after single or split doses of X-rays in C3H/He male mice. The early proliferative response of lung cells after doses which induced lung tumours was also examined after single X-irradiation. The lung-tumour incidence tended to increase with increasing dose after a single irradiation and peaked at 5 Gy. At more than 10 Gy it decreased sharply to the control level. The mean tumour diameters tended to increase with doses up to 7·5 Gy and then decreased beyond 10 Gy. These results suggested that suppression of tumour growth reduced the tumour incidence at doses of over 10 Gy. The lung-tumour incidence decreased with increasing intervals between two equal doses of 2·5 or 5 Gy. The decrease was thought to be caused by the repair of the tumorigenic injury. However, the tumour incidence after two 2·5 Gy irradiations at 1 day intervals or two 5 Gy irradiations at 6 h intervals was higher than that observed after a single dose. This phenomenon was regarded as a progression of the tumorigenic injury. The labelling indices of the lung cells, determined using tritiated thymidine after a single irradiation, were higher than those of non-irradiated control cells. This response was delayed as the dose increased. The responses versus days after irradiation could be classified into three patterns on the basis of their peaks. The possibility that the larger delay after higher doses had some relation to the reduction of target cells for tumour incidence is suggested.     

Effect of cancer chemotherapeutic drugs on the radiation-induced skin reactions in mouse feet

The interactions of seven cancer chemotherapeutic drugs and radiation in normal skin were studied using the mouse foot skin scoring system. Single drug doses were administered 15 min before graded single doses of irradiation or at different intervals before and after a fixed radiation dose. Adriamycin (ADM), bleomycin (BLM), methotrexate (MTX), mitomycin-C (MM-C), and cis-platinum (cis-DDP) all significantly enhanced the radiation-induced skin reactions. The dose-effect factors (DEF) for these drugs ranged from 1.07 to 1.11. Cyclophosphamide (CTX) had a radioprotective effect (DEF 0.90), whereas 5-fluorouracil (5-FU) had no effect (DEF 1.00). The effect of ADM was present at administration from 6 h before to 2 min after irradiation, and the effect of BLM from 24 h before to 4 h after irradiation. The radioprotective effect of CTX and the enhanced effect of MM-C were only present on administration 15 min before and 2 min after irradiation. MTX and cis-DDP enhanced the skin reactions only when given before irradiation.     

Influence of the Leaf Extract of Mentha arvensis Linn. (Mint) on the Survival of Mice Exposed to Different Doses of Gamma Radiation

BACKGROUND: The aim of the present study was to evaluate the radioprotective effect of Mentha arvensis (mint) on the survival of mice exposed to various doses of whole-body gamma radiation. MATERIAL AND METHODS: The radioprotective effect of various doses (0, 2.5, 5, 10, 20, 40 and 80 mg/kg body weight) of chloroform extract of mint (Mentha arvensis Linn.) was studied in mice exposed to 10 Gy gamma radiation. RESULTS: The 10 mg/kg of mint extract was found to afford best protection as evidenced by the highest number of survivors in this group at 30 days post-irradiation, and further experiments were carried out using this dose of mint extract. The mice treated with 10 mg/kg body weight mint extract or oil were exposed to 6, 7, 8, 9 and 10 Gy of gamma radiation and observed for the induction of radiation-sickness and mortality up to 30 days post-irradiation. The mint extract pretreatment was found to reduce the severity of symptoms of radiation sickness and mortality at all exposure doses and a significant increase in the animal survival was observed when compared with the oil + irradiation group. All of the animals that were treated with 10 mg/kg mint extract and then exposed to 7 Gy irradiation were protected against the radiation-induced mortality when compared with the concurrent oil + irradiation group, in which 20% animals died by 30 days post-irradiation. The mint extract treatment protected the mice against the gastrointestinal death as well as bone marrow deaths. The DRF was found to be 1.2. The drug was non-toxic up to a dose of 1,000 mg/kg body weight, the highest drug dose that could be tested for acute toxicity. CONCLUSION: From our study it is clear that mint extract provides protection against the radiation-induced sickness and mortality and the optimum protective dose of 10 mg/kg is safe from the point of drug-induced toxicity.     

Radiation doses for pregnant women in the late pregnancy undergoing fetal-computed tomography: a comparison of dosimetry and Monte Carlo simulations

The purposes of this study were (1) to compare the radiation doses for 320- and 80-row fetal-computed tomography (CT), estimated using thermoluminescent dosimeters (TLDs) and the ImPACT Calculator (hereinafter referred to as the “CT dosimetry software”), for a woman in her late pregnancy and her fetus and (2) to estimate the overlapped fetal radiation dose from a 320-row CT examination using two different estimation methods of the CT dosimetry software. The direct TLD data in the present study were obtained from a previous study. The exposure parameters used for TLD measurements were entered into the CT dosimetry software, and the appropriate radiation dose for the pregnant woman and her fetus was estimated. When the whole organs (e.g., the colon, small intestine, and ovaries) and the fetus were included in the scan range, the difference in the estimated doses between the TLD measurement and the CT dosimetry software measurement was <1 mGy (<23 %) in both CT units. In addition, when the whole organs were within the scan range, the CT dosimetry software was used for evaluating the fetal radiation dose and organ-specific doses for the woman in the late pregnancy. The conventional method using the CT dosimetry software cannot take into account the overlap between volumetric sections. Therefore, the conventional method using a 320-row CT unit in a wide-volume mode might result in the underestimation of radiation doses for the fetus and the colon, small intestine, and ovaries.     

A noninvasive scintigraphic assessment of the colonic transit of nondigestible solids in man

A noninvasive, scintigraphic technique for quantifying large intestinal transit time that provides low radiation doses was developed. The scintigraphic large intestinal transit (SLIT) method uses a total of 100 microCi of 111In encapsulated in ten 2-cm nondigestible capsules, which are ingested after a 6-hr fast. Two hundred fifty microcuries of 99mTc-sulfur colloid were given to outline the gastrointestinal tract. Images were acquired at 4-hr intervals until all capsules were excreted. Normal volunteers (n = 10) consumed a standardized diet 2 days prior and during imaging. Segmental transit times were measured in the following: ascending, transverse, descending, recto-sigmoid colons; hepatic and splenic flexures. The radiation absorbed dose to the large intestine for the SLIT technique is less than half of that associated with other radiographic methods of colonic transit time measurement.     

Chromosome protection by WR-2721 and MPG-single and combination treatments

The radioprotective action of thiol compounds 2-mercaptopropionylglycine (MPG) and S-2(aminopropylamino) ethyl phosphorothioic acid (WR-2721) was evaluated either alone or in combination on the bone marrow chromosomes of Swiss albino mice after 4.5 Gy of 60Co radiation. Single drug administration of WR-2721 at 300 mg/kg body weight resulted in a 50% reduction in the yield of aberrant cells at 24 hours post irradiation, while the other single drug doses were less effective. The combination of the two drugs increased the effect in the sense that 150 mg/kg WR-2721 with 20 mg/kg MPG gave equal protection as 300 mg/kg WR-2721 given alone. Moreover, on day 14, when WR-2721 produced an increase in the precent aberrant cells the above combination brought down the value to normal. It appears that MPG neutralizes to some extent the toxic effect of WR-2721, without impairing the protective efficiency.     

Response of murine small intestine to combined treatment with fostriecin and X rays

This radiobiological investigation was based on the measurements of crypt cell survival in mouse small intestine when the animals were injected with a single dose of fostriecin or streptomycin, and subsequently irradiated to the whole body with graded doses of X rays. The experimental data obtained indicated that fostriecin decreased the isoeffect dose to murine intestine by a factor of 2.3, whereas streptomycin did not influence the radiation response. The biological effects of fostriecin on various tumour cell systems in vitro and in vivo are briefly reviewed. The possible basic mechanisms involved in the radiosensitizing action of fostriecin and the implications of these results in the radiation protection of normal tissues are discussed.     

A comparative study of thoracic radiation doses from 64-slice cardiac CT

The goal of this study was to measure radiation doses for 64-slice cardiac CT angiography studies and to study the dose-savings features of these CT scanners. This was done using various phantoms. These radiation doses were compared with those from typical helical body CT scans, fluoroscopy cardiac catheterization studies and mammography examinations. Radiation measurements were made with a CT ionization detector and a solid state dosimeter. A GE 64-slice Lightspeed VCT and a Siemens Somatom Sensation 64 CT were used to scan a standard 32 cm acrylic phantom and an anthropomorphic phantom. Data were collected in axial and various gated cardiac helical modes. Organ doses and the effective doses were calculated from the measurements. In gated CT cardiac mode with the 32 cm acrylic phantom, the measured radiation doses per study were generally three to seven times greater than those from typical body helical CT examinations; the range depended upon selectable scan parameters. With the anatomical phantom, the surface doses in the anteroposterior (AP) plane were typically 20-60% higher than those measured using the 32 cm phantom. The lateral surface doses were -4% to +15%. These results can be attributed to the shorter AP dimension and the air in the lungs. The CT skin entrance radiation doses were 80-90% less than diagnostic cardiac catheterization studies, and organ doses were similar. Because 64-slice cardiac gated CT uses pitches equal to 0.20-0.27 and high mAs values, the patient radiation doses are appreciably higher than in routine body CT examinations. The female breast, which could receive a radiation dose 10-30 times that received from mammography screening, is an organ of particular concern.     

Increased body weight in C57BL/6 female mice after exposure to ionizing radiation or 60Hz magnetic fields

Purpose: The purpose of this investigation was to determine whether early treatment with ionizing radiation and/or chronic magnetic field (MF) exposure affected body weight in female mice. Materials and methods: Weanling C57BL/6 female mice were irradiated with four equal weekly cobalt-60 exposures (total cumulative doses: 3.0, 4.0, 5.1Gy) and/or received chronic lifetime exposure to 1.4mT 60 Hz circularly polarized MF or ambient MF. The body weights of 2280 mice were recorded at 35 age intervals, and analysis of variance was used to compare the mean differences from baseline weights between treatment groups and sham-exposed controls. Results: A highly statistically significant effect of ionizing radiation on body weight was observed at 28 age intervals (p h 0.001), and for MF exposure at 10 age intervals (p h 0.001). During the young adult growth phase, mice exposed only to MF exhibited h 0.5g greater weight gain relative to sham-exposed controls (p = 0.0001). The effect of ionizing radiation alone was inversely related to dose, with the largest weight increases observed in all of the irradiated groups after 9-12 months (p = 0.0001). Conclusions: Treatment with split-dose ionizing radiation at an early age and chronic exposure to a residential power frequency MF were found to produce small but significant increases in body weight.     

Increased body weight in C57BL/6 female mice after exposure to ionizing radiation or 60Hz magnetic fields

PURPOSE: The purpose of this investigation was to determine whether early treatment with ionizing radiation and/or chronic magnetic field (MF) exposure affected body weight in female mice. MATERIALS AND METHODS: Weanling C57BL/6 female mice were irradiated with four equal weekly cobalt-60 exposures (total cumulative doses: 3.0, 4.0, 5.1Gy) and/or received chronic lifetime exposure to 1.4 mT 60 Hz circularly polarized MF or ambient MF. The body weights of 2280 mice were recorded at 35 age intervals, and analysis of variance was used to compare the mean differences from baseline weights between treatment groups and sham-exposed controls. RESULTS: A highly statistically significant effect of ionizing radiation on body weight was observed at 28 age intervals (p < or = 0.001), and for MF exposure at 10 age intervals (p < or = 0.001). During the young adult growth phase, mice exposed only to MF exhibited < or =0.5 g greater weight gain relative to sham-exposed controls (p = 0.0001). The effect of ionizing radiation alone was inversely related to dose, with the largest weight increases observed in all of the irradiated groups after 9-12 months (p = 0.0001). CONCLUSIONS: Treatment with split-dose ionizing radiation at an early age and chronic exposure to a residential power frequency MF were found to produce small but significant increases in body weight.