Radiobiology and clinical application of halogenated pyrimidine radiosensitizers

Halogenated pyrimidines (HP) represent a unique class of non-hypoxic cell radiosensitizers currently under clinical re-investigation. In order for halogenated pyrimidines to sensitize cells to radiation, they must be incorporated into cellular DNA. In the case of human tumors, which have in general rather long cell cycle times, this may require many days of continuous drug infusion to achieve adequate replacement of the DNA base thymidine with HP. In vitro studies support the relationship between the extent of radiosensitization and the percentage of thymidine replacement. Recent clinical studies evaluating the role of iododeoxyuridine (IdUrd) as a radiation sensitizer in large unresectable sarcomas have been extremely encouraging. To support and expand upon these positive clinical findings more information and research is needed regarding: (1) the mechanism of HP-induced radiosensitization; (2) the percentage of HP thymidine replacement in human tumors achievable and how it relates to treatment outcome; (3) the means of increasing HP incorporation in tumor and minimizing incorporation in normal tissues; (4) a better understanding of optimal timing between HP administration and radiation treatment; and (5) methods to evaluate which tumors are appropriate candidates for HP therapy. While presently limited to use in conventional high dose-rate X-ray therapy, laboratory studies suggest that HP might also be effective in low dose-rate brachytherapy and for selected high LET clinical beams. HPs probably will not be 'general' non-hypoxic cell radiosensitizers for all tumor types, but with appropriate tumor-type/anatomical site selection and refinement in their administration, HPs may prove beneficial in cancer treatment.     

Gamma Radiation Response and Recovery Studies in Radiation Sensitive Mutants of Diploid Yeast

Summary

Cell killing and other deleterious biological effects of ionizing radiation are the result of chemical changes to critical targets, initiated at the time of exposure. Electron-affinic radiosensitizers act, primarily, by chemically modifying this radiation damage and its consequent biological expression, and such changes can be used to probe the nature of the cellular radiation target. According to a redox hypothesis of radiation modification, the molecular mechanism of electronic-affinic radiosensitization involves an oxidative interaction of the sensitizer with reactive, potentially damaging target radicals, which competes with reductive processes that restore the target to its undamaged state.

The effects have been compared of a series of hypoxic cell radiosensitizers on radiation-induced DNA damage and mammalian cell killing, in order to ascertain the nature of the critical radiation target site(s) involved. Sensitizer efficacy is determined by the ability to oxidize the radiation target and is found to increase exponentially with increasing electron affinity. The threshold redox potential, below which no sensitization occurs, corresponds to the oxidation potential of the target bioradical involved, and is characteristic, and useful in identification, of the particular radiation target.

Model product analysis studies of DNA base damage, inorganic phosphate release, single-strand breaks and incorporation of radioactively labelled sensitizer into DNA show a correspondence between the electronic-affinic radiosensitization of DNA damage and cell killing. A careful comparison of the radiosensitization of different DNA sites and cell killing indicates that the sugar-phosphate backbone of DNA, not the heterocyclic bases, is the DNA target site which mimics cell killing in its threshold redox potential and overall radiosensitization response. These results suggest that the enhancement by electron-affinic drugs of radiation damage to the DNA backbone (strand breaks) correlates strongly with, and is the most likely cause of, the radiosensitization of hypoxic cell killing.     

放射增敏剂在肿瘤治疗中的应用

放射治疗是治疗恶性肿瘤的重要手段之一。临床上常因正常组织耐受剂量的限制而不能给予肿瘤足够的照射剂量,而造成治疗失败,因此,如何提高肿瘤对射线的敏感性是临床肿瘤放疗面临的突出问题。放射增敏剂作为一种增强肿瘤放疗敏感性、提高放疗疗效的药物,通过增加辐射诱导的氧自由基及DNA损伤、调控放疗关键分子靶点以达到放射增敏目的。本文结合放射增敏剂在放射治疗中的应用,概述了放射增敏剂的发展现状及相关领域的研究进展,并对多种放射增敏剂的作用机制进行了简要综述,以期为进一步研究放射增敏调控的分子机制、促进放射增敏剂的研发,以及设计新的策略改善放射治疗结果提供帮助。     

Chromosome aberrations detected by FISH and correlation with cell survival after irradiation at various dose-rates and after bromodeoxyuridine radiosensitization

PURPOSE: To determine whether measurement of chromosome aberrations by fluorescence in situ hybridization (FISH) predicts cell survival after irradiation at different dose-rates and after radiosensitization by bromodeoxyurdine (BrdU) in a lung carcinoma cell line. MATERIALS AND METHODS: The human lung carcinoma cell line SW1573 was irradiated at high dose-rate (HDR: 0.8 Gy min-1) or at pulsed low dose-rate (p-LDR: average dose-rate 1 Gy h-1) with or without radiosensitization by bromodeoxyuridine (BrdU). Cell survival was determined by clonogenic assay. Chromosome aberrations (colour junctions) were measured by whole-chromosome FISH of chromosome 2 and 18 and were scored according to the PAINT method. RESULTS: Clear radiosensitization by BrdU was observed both after HDR and p-LDR irradiation. Chromosome 18 was more radiosensitive than chromosome 2. There was a good correlation between induction of colour junctions and cell survival both after HDR and p-LDR irradiation and after radiosensitization by BrdU. CONCLUSIONS: Determination of chromosome aberrations by FISH can predict cell survival after different dose-rates and after radiosensitization by BrdU     

高分子纳米材料用于肿瘤放疗增敏的研究进展

放疗是治疗恶性肿瘤的三大常规手段之一,但由于其存在高辐射剂量损伤正常组织和肿瘤细胞辐射抵抗性强等问题,导致治疗后往往达不到预期效果。为提高放疗疗效,并且减少对正常组织的不良作用,探索新型放疗增敏剂及放化疗联合的新策略已成为研究热点。高分子纳米材料凭借其良好的生物相容性和生理稳定性等优点,为提高肿瘤放疗效果开拓了广阔的应用前景。笔者就高分子纳米材料用于放疗增敏的研究进展进行综述。     

Effect of p53 activation on cell growth, thymidine kinase-1 activity, and 3'-deoxy-3'fluorothymidine uptake

The use of thymidine (TdR) and thymidine analogs such as 3'-deoxy-3'-fluorothymidine (FLT) as positron emission tomography (PET)-based tracers of tumor proliferation rate is based on the hypothesis that measurement of uptake of these nucleosides, a function primarily of thymidine kinase-1 (TK(1)) activity, provides an accurate measure of cell proliferation in tumors. Tumor growth is influenced by many factors including the oxygen concentration within tumors and whether tumor cells have been exposed to cytotoxic therapies. The p53 gene plays an important role in regulating growth under both of these conditions. The goal of this study was to investigate the influence of p53 activation on cell growth, TK(1) activity, and FLT uptake. To accomplish this, TK(1) activity, S phase fraction, and the uptake of FLT were determined in plateau-phase and exponentially growing cultures of an isogenic pair of human tumor cell lines in which p53 expression was normal or inactivated by human papilloma virus type 16 E6 expression. Ionizing radiation exposure was used to stimulate p53 activity and to induce alterations in cell cycle progression. We found that exposure of cells to ionizing radiation induced dose-dependent changes in cell cycle progression in both cell lines. The relationship between S phase percentage, TK(1) activity, and FLT uptake were essentially unchanged in the p53-normal cell line. In contrast, TK(1) activity and FLT uptake remained high in the p53-deficient variant even when S phase percentage was low due to a p53-dependent G2 arrest. We conclude that a functional p53 response is required to maintain the normal relationship between TK1 activity and S phase percentage following radiation exposure.     

Gold nanoparticles in combination with megavoltage radiation energy increased radiosensitization and apoptosis in colon cancer HT-29 cells

Purpose: Gold nanoparticles (GNP) act as a radiosensitizer in radiation therapy. However, recent studies have shown contradictory evidence in terms of radiosensitization in the presence of GNP combined with X-ray megavoltage energy (MV) on different cell types. In this study, the effect of GNP on radiosensitization enhancement of HT-29 human colorectal cancer cells at MV X-ray energy was evaluated.

Materials and methods: The cytotoxicity and radiosensitization of GNP were evaluated in HT-29 human colorectal cancer cells by MTS-assay and multiple MTS-assay, respectively. Cellular uptake was assayed using graphite furnace atomic absorption spectrometry (GFAAS). Apoptosis and cell cycle progression were determined by an Annexin V-FITC/propidium iodide (PI) kit and PI/RNase solution with flow cytometry, respectively.

Results: Results showed that the cell viability of the HT-29 cells was not influenced by exposure to different concentrations of GNP (10–100 μM). GNP alone did not affect the cell cycle progression and apoptosis. In contrast, GNP, in combination with radiation (9?MV), induced more apoptosis. The interaction of GNP with MV energy resulted in a significant radiosensitization enhancement compared with irradiation alone.

Conclusion: It was concluded that GNP may work as bio-inert material on HT-29 cancer cells and their enhancement of radiosensitization may be due to increase in the absorbed irradiation dose.     

Physical heights of children with prolonged low dose-rate γ-radiation exposure in radiocontaminated buildings

Purpose : To evaluate low dose-rate radiation effects on the physical heights of children staying in apartments with 60 Co-contaminated steel construction. Materials and methods : Children who once resided in radiocontaminated apartments since early 1983 were examined for height and body weight status from age 1 month to 18 years and before they moved out of the apartments. The physical heights and body weights of 21 898 age- and sex-matched non-exposed children from a nationwide school surveillance in 1997-98 were taken as controls. The physical height data were shown as height percentiles (HP) compared with reference children and agespecific relative height differences (RHD). Results : HP and RHD in 48 exposed boys and 37 girls were analysed using generalized estimating equations (GEE), which accounted for multiple measurements and correlation between these measurements in the same individuals during this period. After adjusting for effects from parental heights and body mass index (BMI), clear dose-related decreases in HP and RHD were observed in the exposed boys with a cumulative exposure > 60 mSv. Conclusions : Prolonged low dose-rate γ-radiation exposure was associated with adverse effects on the physical heights of growing boys, but were less apparent in the exposed girls.     

Hypoxia-selective Radiosensitization of Mammalian Cells by Nitracrine,an Electron-affinic DNA Intercalator

Summary

The radiosensitizing ability of the 1-nitroacridine nitracrine (NC) is of interest since it is an example of a DNA intercalating agent with an electron-affinic nitro group. NC radiosensitization was evaluated in Chinese hamster ovary cell (AA8) cultures at 4°C in order to suppress the rapid metabolism and potent cytotoxicity of the drug. Under hypoxic conditions, submicromolar concentrations of NC resulted in sensitization (SER = 1·6 at 1 µmol dm^?3). Sensitization was also seen under aerobic conditions but a concentration more than 10-fold higher was required. In aerobic cultures NC radiosensitization was independent of whether cells were exposed before and during, or after, irradiation. Postirradiation sensitization was not observed under hypoxic conditions. The time dependence of NC uptake and the development of radiosensitization were similar (maximal at 30 min at 4°C under hypoxia) suggesting that sensitization, unlike cytotoxicity, is due to unmetabolized drug. NC is about 1700 times more potent as a radiosensitizer than misonidazole. This high potency is adequately accounted for by the electron affinity of NC (E(1) value at pH 7 of ?275mV versus NHE) and by its accumulation in cells to give intracellular concentrations approximately 30 times greater than in the medium. However, concentrations of free NC appear to be low in AA8 cells, presumably because of DNA binding. If radiosensitization by NC is due to bound rather than free drug, it suggests that intercalated NC can interact very efficiently with DNA target radicals. This is despite a binding ratio in the cell estimated as less than 1 NC molecule/400 base pairs under conditions providing efficient sensitization. This work suggests a new approach in the search for more effective clinical radiosensitizers, and poses questions on the means by which intercalated drugs can interact with DNA damage.     

Radioactivity in Man

Summary

We have estimated the rate of unscheduled DNA synthesis (UDS) in human lymphocytes from measurements of tritiated thymidine incorporation into double-stranded DNA (ds-DNA) during incubation of cells in vitro. Cells were not subjected to stresses except those associated with careful handling, or in certain experiments, mild heating or treatment with phytohaemagglutinin (PHA). Contribution of scheduled DNA synthesis (SDS) to incorporation was reduced by inhibiting replication and separating freshly replicated single-stranded DNA from repaired ds-DNA by chromatography. By increasing the incubation temperature, which decreases SDS and increases UDS, the residual contribution of scheduled DNA synthesis to thymidine incorporation into ds-DNA was estimated. Effects of increasing the number of cells in S-phase by phytohaemagglutinin were also investigated. Results suggest that: the rate of unscheduled DNA synthesis is about 500 ± 100 thymidine molecules incorporated per cell per hour; a temperature-sensitive process, probably hydrolysis of DNA, contributes much of the damage repaired by UDS; background ionizing radiation contributes little to the damage; and damage caused by DNA hydrolysis is repaired much more efficiently than lethal damage caused by ionizing radiation. Large increases in incorporation into ds-DNA occurred when cells were stimulated with PHA.     

Physical heights of children with prolonged low dose-rate gamma-radiation exposure in radiocontaminated buildings

PURPOSE: To evaluate low dose-rate radiation effects on the physical heights of children staying in apartments with 60Co-contaminated steel construction. MATERIALS AND METHODS: Children who once resided in radiocontaminated apartments since early 1983 were examined for height and body weight status from age 1 month to 18 years and before they moved out of the apartments. The physical heights and body weights of 21 898 age- and sex-matched non-exposed children from a nationwide school surveillance in 1997-98 were taken as controls. The physical height data were shown as height percentiles (HP) compared with reference children and age-specific relative height differences (RHD). RESULTS: HP and RHD in 48 exposed boys and 37 girls were analysed using generalized estimating equations (GEE), which accounted for multiple measurements and correlation between these measurements in the same individuals during this period. After adjusting for effects from parental heights and body mass index (BMI), clear dose-related decreases in HP and RHD were observed in the exposed boys with a cumulative exposure > 60 mSv. CONCLUSIONS: Prolonged low dose-rate y-radiation exposure was associated with adverse effects on the physical heights of growing boys, but were less apparent in the exposed girls.     

The use of theranostic gadolinium-based nanoprobes to improve radiotherapy efficacy

A new efficient type of gadolinium-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy (RT). These new particles consist of a polysiloxane network surrounded by a number of gadolinium chelates, usually 10. Owing to their small size (<5 nm), AGuIX typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes. For example, although a significant proportion of these particles accumulate in tumours, the remainder is rapidly eliminated by the renal route. In addition, in the absence of irradiation, the nanoparticles are well tolerated even at very high dose (10 times more than the dose used for mouse treatment). AGuIX particles have been proven to act as efficient radiosensitizers in a large variety of experimental in vitro scenarios, including different radioresistant cell lines, irradiation energies and radiation sources (sensitizing enhancement ratio ranging from 1.1 to 2.5). Pre-clinical studies have also demonstrated the impact of these particles on different heterotopic and orthotopic tumours, with both intratumoural or intravenous injection routes. A significant therapeutical effect has been observed in all contexts. Furthermore, MRI monitoring was proven to efficiently aid in determining a RT protocol and assessing tumour evolution following treatment. The usual theoretical models, based on energy attenuation and macroscopic dose enhancement, cannot account for all the results that have been obtained. Only theoretical models, which take into account the Auger electron cascades that occur between the different atoms constituting the particle and the related high radical concentrations in the vicinity of the particle, provide an explanation for the complex cell damage and death observed.Radiotherapy (RT) is the most commonly used non-surgical cancer therapy, designed to apply ionizing radiation at a sufficiently high cytotoxic dose to kill cells within the tumour tissue.¹ RT is primarily limited in its ability to deliver therapeutic doses to the target tumour volume whilst minimizing damage to the surrounding healthy tissue.² Numerous solutions have been proposed to overcome this issue, broadly falling into two main categories: (i) implementation of advanced RT techniques enabling intensity-modulated radiation fields [intensity-modulated radiation therapy (IMRT)] in order to more precisely adapt the dose to the tumour target; (ii) development of a new generation of therapeutic agents that sensitize cells to ionizing radiation (radiosensitizers) by improving dose efficacy with their high density and high atomic number (Z).³ High atomic number compounds may provide further benefit in the clinical setting by improving contrast properties for radiological imaging. This would allow monitoring of the radiosensitizing agent within the tumour. It would also facilitate precise defining of the tumour target to allow radiosensitization without affecting healthy tissue. These types of agents are known as “theranostic” agents.Classical imaging contrast agents based on iodine for CT and gadolinium complexes for MRI could all potentially prove effective theranostic agents. The use of inorganic nanoparticles for radiosensitization was first demonstrated by Hainfeld et al⁴ using 1.9-nm gold nanoparticles delivered systemically prior to irradiation in mice exhibiting EMT-6 mammary carcinomas. The authors reported 1-year survival in 86% of animals treated under these conditions compared with only 20% in those irradiated without gold particle injection. The interest in researching inorganic nanoparticles for the purposes of radiosensitization stems from the unique properties of these particles. Firstly, their innate high atomic number and density characteristics, lending them higher mass energy absorption coefficients than soft tissues;⁵ secondly, their multimodality offering the potential for theranostic applications, such as obtaining imaging functionality in addition to radiosensitizing properties;⁶ thirdly, their particular morphology that enables tailored biodistribution, with the potential for passive targeting due to the enhanced permeability and retention (EPR) effect.⁷ In recent studies, nanoparticles have been shown to induce a highly heterogeneous energy distribution at the subcellular scale, leading to complex cell damage near the particles.⁸ This could be a key factor in determining overall response.Despite the efficacy of gold particles as radiosensitizers, gold may not be the only suitable high atomic number theranostic candidate, given the lack of sensitivity afforded by CT classically using gold nanoparticles. The combination of MRI and RT technologies for a single image-guided treatment holds clear potential for improved clinical outcome, as emphasized by the development of new fused instruments combining these two modalities. In this context, gadolinium-based particles appear particularly interesting, since their MRI contrast properties are significantly higher than those of molecular complexes in current use, and they also present a strong and promising radiosensitizing effect.     

Weiss Lecture

Summary

The dose-rate effect has been the topic of extensive radiobiological studies and has important implications in radiation therapy and in the field of radiation protection. Three examples will be discussed: two in radiation therapy and one in protection. First, continuous low dose-rate interstitial brachytherapy may be replaced by pulsed brachytherapy, using a single source moving through the catheters of the implant. This strategy, using a modern computer-controlled afterloading device, would allow better dose optimization and result in a considerable cost saving. Radiobiological data have proved useful in defining the pulse length and pulse frequency that is equivalent to continuous low dose-rate. Second, in the intracavitary treatment of carcinoma of the cervix, a few high dose-rate (HDR) fractions on an outpatients basis can replace the low dose-rate (LDR) treatment that requires the patient to be hospitalized for several days. Radiobiological data can be used to estimate the dose levels at HDR that are equivalent to conventional LDR protocols. Third, it is usually assumed in radiation protection that doses accumulated over a period of time at low dose-rate are less effective biologically than the same dose delivered in a single acute exposure. While this may be true for X- or γ-rays, radiobiological data indicate that neutrons delivered at low dose or in a series of fractions spread out over a period of time may produce more oncogenic transformation than a single acute exposure. This has important implications in radiation protection.     

Changes in Cellularity Induced by Radiation in a Solid Tumour

The growth and cellular responses of Morris hepatoma 3924 A to a locally-administered dose of 3750 R X-rays were studied using the following parameters: (1) relative tumour volume changes; (2) tritiated thymidine (³H-TdR) incorporation into DNA; (3) tumour DNA content and (4) cellular analysis, including ³H-TdR labelling index, mitotic index, aberrant mitotic frequency and relative cell density. Before depression of tumour growth, cell proliferation is temporarily interrupted. As proliferation is reinitiated, a short-lived synchrony and prolongation of cell-cycle traverse are reflected in (a) the labelling index and mitotic index, (b) the relative cell density, and (c) the rate of incorporation of ³H-TdR into DNA. Within 4 days after radiation, cell proliferation and ³H-TdR incorporation are significantly depressed. Simultaneously there are reductions in both the relative cell density and tumour DNA contents, and these remain depressed as the tumours initiate regression. From these studies, it is apparent that the cellular responses to radiation insult occur well in advance of measurable volume changes and are observed both in tumours that continue to regress and in those that initiate regrowth.     

Radiosensitization of tumour cells by cantharidin and some analogues

PURPOSE: Mammalian cells at mitosis contain chromatin in compacted form and are hypersensitive to ionizing radiation. Previous research had shown some chemicals that induce chromatin compaction within interphase cells act as radiosensitizers. Of these agents, cantharidin (LS-1), which is an inhibitor of protein phosphatases 1 (PP1) and 2A (PP2A), showed good radiosensitizing activity at non-toxic doses. Cantharidin and 13 additional structural analogues (LS-2-14) were tested for their radiosensitizing activity on tumour cells in vitro. MATERIALS AND METHODS: Twelve of the 14 cantharidin analogues were synthesized in the authors' laboratory. Various concentrations of the drugs were screened for toxicity and radiosensitizing effectiveness with asynchronous DU-145 (human prostate carcinoma) cells. More detailed radiobiological studies of the more potent agents were performed with HT-29 (human colon carcinoma) cells since they could be readily synchronized. The radiosensitization of G1 phase HT-29 cells was measured after a 2-h exposure to the more potent drugs and reductions of the surviving fraction after an acute dose of 2 Gy (SF2Gy) served to estimate their relative effectiveness. The increase in phosphorylation of histone 1 (H1) and histone 3 (H3) induced by these drug exposures was measured by Western blotting of protein extracts. Drug-induced change in chromatin morphology was visualized by electron microscopy, and the alkaline comet assay (which measures DNA single-strand breaks) was employed to measure the radiation sensitivity of cellular chromatin in the drug-treated cells. RESULTS: Of the 14 cantharidin analogues tested, LS-1, LS-2 and LS-5 at concentrations of 3-20 microM showed little or no toxicity, produced elevated levels of H1 and H3 phosphorylation, and effected significant radiosensitization at low radiation dose. The chromatin in tumour cells treated with LS-5 became visibly compacted and its DNA was about 1.6 times more sensitive to radiation-induced strand breakage relative to that of control cells. CONCLUSIONS: The results confirm the authors' earlier studies that showed an increase in tumour cell intrinsic radiosensitivity by exposure to agents that promote chromatin compaction. LS-5 was identified as the optimal radiosensitizing agent of this class of compounds. Radiosensitization was correlated with chromatin compaction and elevated phosphorylation of H1 and H3. The DNA in drug-treated cells exhibited an enhanced sensitivity to radiation-induced single-strand breakage.     

碳离子放疗与化疗药物联合应用的生物学效应

碳离子放射治疗（carbon ion radiotherapy,CIRT）属于高线性能量传递（higher linear energy transfer,LET）射线。碳离子射线不但具有适合肿瘤放射治疗的物理剂量分布特征（Bragg峰）,而且主要通过导致肿瘤细胞DNA的双链断裂杀灭肿瘤细胞,因此较光子射线具更强的生物学效应,对肿瘤细胞具有更强的杀灭作用。化疗药物与光子放射治疗的联合治疗是目前广泛应用于肿瘤治疗的策略。化疗与放疗的同期应用主要基于其增敏作用。然而,化疗药物是否能增敏碳离子放疗的抗肿瘤效应而不仅仅是叠加效应,目前尚未明确。本文将基于对基础生物学研究（包括细胞学实验及动物实验）到临床研究结果的分析,详细阐述肿瘤碳离子放疗与化疗药物联合治疗的生物学效应。     

近距离治疗的临床放射生物学

近距离治疗是将放射性同位素植入或置于肿瘤周边的一种技术。中心高剂量及随着距离的增加剂量迅速衰减是其最大的特点。近距离治疗主要包括低剂量率、高剂量率和脉冲剂量率3种。近距离治疗的最大优势是保证肿瘤组织充足剂量的基础上降低周围正常组织的放射性损伤。临床近距离治疗技术的进步与其放射生物学特点联系紧密。临床近距离治疗放射生物学的基本概念主要包括剂量率效应、放射性损伤的修复、再氧合、细胞周期的再分布及再群体化。探索近距离治疗放射生物学与临床近距离治疗效果的关系,利用近距离治疗的放射生物学特点,指导临床上近距离治疗的具体应用需要大量转化医学的工作。最终的目的是增加肿瘤局部控制率、降低不良反应及提高患者最终的生存期。     

Treatment of Radioresistant Cancers–Proceedings of the International Symposium on the Prospects for Treatment of Radioresistant Cancers Held in Kyto (Japan), May 21st 1979

Summary

Using autoradiographic methods it was noted that S phase cells at the bottom of the crypts in the small intestine were the most efficient scavengers of exogenous injected thymidine. The efficiency of the incorporation of ³H-TdR (salvage pathway of DNA synthesis) by cells at the crypt base (stem cell zone) was twice as high as for the S phase cells at the top of the crypt (maturing proliferative cells). There were no such position-dependent differences in incorporation of ³H-UdR (de novo pathway of DNA synthesis). Radiation (0·75–5·0 Gy ¹³⁷Cs γ-rays) inhibited the incorporation of ³H-TdR very rapidly and this was also cell-position dependent. The cells at the bottom of the crypt were the most affected. The injection of cold thymidine before ³H-TdR changed the pattern of the incorporation of ³H-TdR along the side of the crypt in a very similar way to radiation, and the grain number was decreased predominantly in the cells at lower positions.

The possibility of the existence of a regional gradient of endogenous thymidine (reutilization from intestinal sources), and the influence of irradiation on the gradient of thymidine incorporation resulting from direct and abscopal effects of whole body exposure, are discussed.     

Meta-analysis of non-tumour doses for radiation-induced cancer on the basis of dose-rate

Purpose: Quantitative analysis of cancer risk of ionising radiation as a function of dose-rate. Materials and methods: Non-tumour dose, D(nt), defined as the highest dose of radiation at which no statistically significant tumour increase was observed above the control level, was analysed as a function of dose-rate of radiation. Results: An inverse correlation was found between D(nt) and dose-rate of the radiation. D(nt) increased 20-fold with decreasing dose-rate from 1-10(-8) Gy/min for whole body irradiation with low linear energy transfer (LET) radiation. Partial body radiation also showed a dose-rate dependence with a 5- to 10-fold larger D(nt) as dose rate decreased. The dose-rate effect was also found for high LET radiation but at 10-fold lower D(nt) levels. Conclusions: The cancer risk of ionising radiation varies 1000-fold depending on the dose-rate of radiation and exposure conditions. This analysis explains the discrepancy of cancer risk between A-bomb survivors and radium dial painters.     

Imaging features of paediatric haemophilic pseudotumour of the maxillary bone: report of three cases and review of the literature

Objectives

: Haemophilic pseudotumour (HP) is an extremely rare lesion. The purpose of this study was to describe the CT and MRI features of maxillary bone HPs and introduce the key points to differentiate HP from the mimicking entities in the region.

Methods

: We retrospectively reviewed three paediatric patients with histology-proven HPs arising from the maxillary bone. All three patients underwent CT and/or MRI. Combined with six previously reported cases in the literature, the imaging features were comprehensively analysed.

Results

: All HPs showed a well-demarcated, multilobulated expansile osteolytic lesion in the maxillary bone. On non-enhanced CT, HPs appeared of mixed density relative to grey matter. The lesions appeared to have markedly heterogeneous signal intensity on both T₁ and T₂ weighted images, with septa-like enhancement following the administration of contrast material, which corresponded to blood products in various stages of evolution. The lesions caused cortical thinning and even focal disappearance and multiple bone septa were identified within the involved maxillary bone. Some HPs were associated with radiated periosteal proliferation, which can easily be misdiagnosed as a malignant bone tumour.

Conclusion

: A high index of suspicion for HP and a familiarity with imaging findings may help to accurately diagnose this rare entity.Haemophilic pseudotumour (HP) is a rare and serious complication that occurs in 1–2% of patients with severe haemophilia, and most frequently develops in the femur, tibia, pelvic bones, small bones of the hand and, rarely, in the craniofacial bones [1-6]. It is essentially an encapsulated haematoma resulting from repetitive bleeding and is surrounded by a thick, fibrous capsule. To the best of our knowledge, a total of six cases of maxillary bone HPs have been reported in the literature to date [1,2,7-10]; unfortunately, the imaging findings were not described effectively. During the past 10 years, HPs in the maxillary bone have been confirmed by histopathology in three children at our hospital. The imaging findings of these three HPs were retrospectively reviewed and, combined with the literature, the value of using CT and MR imaging to diagnose, treat and follow up patients with HP in the maxillary bone was also discussed.