Detection of the effects of low dose ionising irradiation on epidermal function

A non-invasive technique for the detection of small doses of X irradiation to the skin would be important for improvements in radiation protection. In this investigation we have studied the effects of doses of X rays of less than 2.0 Gy (suberythemal) on human skin in order to select such a technique. Our results indicate that a dose of X rays between 0.5 and 1.0 Gy was sufficient to depress significantly epidermal cell production in the basal layer. Accompanying this change in epidermal cell production after 1.0 Gy exposure, there was a reduction in the rate of desquamation of corneocytes. In the stratum granulosum, changes in "non-specific esterase" activity (a marker of lysosomal enzyme release) were also observed. Thus at three stages of the keratinisation process, functional alterations had occurred within three days of exposure to an X ray dose of 1.0 Gy. For this reason it seems likely that the various changes were at least partially independent of each other and that the stratum corneum may serve as a biological dosimeter for the detection of exposure to low doses of ionising radiation.     

Effect of MR imaging on spleen colony formation following gamma irradiation

This article describes experiments performed to examine the possible effect of interaction between ionizing radiation and magnetic resonance (MR) on damage to normal tissue. Eight-week-old ICR male mice were irradiated (cobalt-60 radiation) with 5, 6, or 7 Gy given either alone or followed by MR imaging. Other groups received fractionated doses of 6 Gy (3 Gy + 3 Gy) or 7 Gy (3 Gy + 4 Gy) either with or without subsequent MR imaging. Ten days after exposure, spleens were assayed for endogenous spleen colonies. The number of spleen colonies was lower at higher radiation doses, and fractionation of the dose resulted in an increase in colony number compared with a comparable dose in a single exposure. No difference was seen, however, between comparable radiation groups that were or were not subjected to MR imaging. In addition to the spleen colony assay, body weights and wet weights for spleen, thymus, and testes were obtained, since these suffer weight loss in proportion to radiation dose. As with the spleen colony assay, no significant effect of MR imaging was observed. These results indicate that for the normal tissues studied, MR imaging neither increases radiation damage nor inhibits repair between fractions.     

Determination of colony numbers in pig epidermis as an estimate for radiosensitivity. A rapid assay based on in vitro BrdU-labelling

A rapid assay has been developed for the quantitation of colonies arising from surviving clonogenic cells in pig epidermis after irradiation. The number of surviving clonogenic cells per unit area was related to the epidermal in vivo response of moist desquamation. After irradiation with single doses, ranging from 20 to 36 Gy, skin biopsies were taken and incubated in dispase for enzymatic separation of the epidermis and dermis. Full thickness epidermal sheets were labelled with bromodeoxyuridine (BrdU) in vitro. Proliferating cells were visualized using standard immunohistochemical procedures. Cell groups containing > or = 16 cells were counted as colonies. These colonies were first seen on day 14/15 after irradiation. The number of colonies per cm2, as a function of skin surface dose, yielded a cell survival curve with a D0 (+/- SE) of 3.87 +/- 0.57 Gy. The ED50 for the epidermal in vivo reaction of moist desquamation corresponded with a colony density of 2.7 colonies per cm2. After higher doses, abundant smaller colonies of 4-8 BrdU-positive cells were seen and these were more radioresistant, as represented by higher D0 values.     

Long-term results of pulsed irradiation of skin metastases from breast cancer. Effectiveness and sequelae.

PURPOSE: The concept of pulsed brachytherapy suggested by Brenner and Hall requires an unusual fractionation scheme. Effectiveness and sequelae of this new irradiation method were observed in patients with disseminated cutaneous metastases of breast cancer. PATIENTS AND METHODS: A flexible, reusable skin mold (weight 110 g) was developed for use with a pulsed dose rate (PDR) afterloader. An array of 18 parallel catheters (2 mm diameter) at equal distances of 10 or 12 mm was constructed by fixation of the catheters in a plastic wire mesh. The array is sewn between 2 foam rubber slabs of 5 mm thickness to provide a defined constant distance to the skin. Irradiations are possible up to a maximum field size of 20 x 23.5 cm using a nominal 37 GBq Ir-192 source. Pulses of 1 Gy reference dose at the skin surface are applied at a rate of 1 pulse every 1.2 hours (0.8 Gy per hour). The dose distribution is geometrically optimized to provide a homogeneous skin dose (100% +/- 10%). The 80% dose level lies at 5 mm below the skin surface. Between April 1994 and December 1997, 52 patients suffering from cutaneous metastases at the thoracic wall were treated with 54 fields and total doses of 38 to 50 Gy (median 42 Gy) applying 2 PDR courses with a pause of 4 to 5 weeks. RESULTS: Forty-six patients (48 fields) were eligible for evaluation in June 1998. The median follow-up was 16 months (range 7.1 to 46.2 months). Local control was achieved in 40 out of 48 fields (83%) or 41 of 46 patients (89%), respectively. Moist desquamation occurred in 52% of the patients. Late reactions were judged after a minimum follow-up of 6 months. Thirty-two fields had been previously irradiated with external beam therapy to doses of 40 to 60 Gy. Regardless of whether the skin was preirradiated or not all patients surviving long enough developed telangiectasia within 2 years after PDR irradiation. In preirradiated patients (n = 32) skin contractures and/or skin necrosis occurred in 12% each. In newly irradiated patients (n = 14) no contractures or skin necrosis were observed. CONCLUSIONS: Pulsed brachytherapy is an effective and time-sparing method for the treatment of cutaneous metastases from breast cancer. Skin reactions are comparable to the sequelae of orthovoltage therapy. Two sessions of approximately 20 Gy PDR were tolerated on preirradiated skin without severe sequelae.     

Single dose irradiation response of pig skin: a comparison of brachytherapy using a single, high dose rate iridium-192 stepping source with 200 kV X-rays

An experimental brachytherapy model has been developed to study acute and late normal tissue reactions as a tool to examine the effects of clinically relevant multifractionation schedules. Pig skin was used as a model since its morphology, structure, cell kinetics and radiation-induced responses are similar to human skin. Brachytherapy was performed using a microSelectron high dose rate (HDR) afterloading machine with a single stepping source and a custom-made template. In this study the acute epidermal reactions of erythema and moist desquamation and the late dermal reactions of dusky mauve erythema and necrosis were evaluated after single doses of irradiation over a follow-up period of 16 weeks. The major aims of this work were: (a) to compare the effects of iridium-192 (192Ir) irradiation with effects after X-irradiation; (b) to compare the skin reactions in Yorkshire and Large White pigs; and (c) to standardize the methodology. For 192Ir irradiation with 100% isodose at the skin surface, the 95% isodose was estimated at the basal membrane, while the 80% isodose covered the dermal fat layers. After HDR 192Ir irradiation of Yorkshire pig skin the ED50 values (95% isodose) for moderate/severe erythema and moist desquamation were 24.8 Gy and 31.9 Gy, respectively. The associated mean latent period (+/- SD) was 39 +/- 7 days for both skin reactions. Late skin responses of dusky mauve erythema and dermal necrosis were characterized by ED50 values (80% isodose) of 16.3 Gy and 19.5 Gy, with latent periods of 58 +/- 7 days and 76 +/- 12 days, respectively. After X-irradiation, the incidence of the various skin reactions and their latent periods were similar. Acute and late reactions were well separated in time. The occurrence of skin reactions and the incidence of effects were comparable in Yorkshire and Large White pigs for both X-irradiation and HDR 192Ir brachytherapy. This pig skin model is feasible for future studies on clinically relevant multifractionation schedules in a brachytherapy setting.     

Late radiation fibrosis in rat lung following protons and 250 kV X-rays irradiation

To investigate the biological effectiveness of proton beams in the development of pulmonary fibrosis the lungs of male 7-week-old Wistar rats were locally irradiated with a single dose of 10-50 Gy of 250 kV X-rays and modulated, 250 MeV protons at Particle Radiation Medical Science Center (PARMS). Animals were sacrificed serially after 3, 6, 9 and 12 months at which times the development of the fibrotic lesion in alveolar walls and peribronchial connective tissues was assessed quantitatively by analysis of microscopic images of Azan-Mallory stained sections. Fibrosis index (FI) values in alveolar walls and peribronchial tissues were defined as the fraction (in percent) of a specific image area, the gray level of which represents collagen deposits. Using this FI values, the increase of fibrotic lesion following 0-40 Gy of X-rays irradiation as a function of time were observed better in alveolar walls than in peribronchial tissues. Compared with 250 kV X-rays, 30 Gy of proton beams irradiation produced less increase in the time course of FI values of alveolar walls and dose-response curve at 12 months later suggested that the fibrotic lesion in alveolar walls after protons exposure of the doses above 30 Gy might develop more slowly.     

The RBE for renal damage after irradiation with 3 MeV neutrons

Mouse kidneys were locally irradiated with single doses or up to 8 fractions of 240 kV X rays or 3 MeV neutrons. Damage was assessed from measurements of urine output, isotope clearance or haematocrit levels. All three assays gave steep dose-response curves by 4-5 months after irradiation. The repair capacity of the kidney was considerable after X-irradiation but was very small after irradiation with neutrons. Thus the RBE increased sharply with increasing fractionation. After large doses, an RBE of 2.3-2.5 was measured, rising to 4.5-5.1 after 8 fractions of 4 to 5 Gy X rays. Linear-quadratic analysis of these data has allowed RBE's to be calculated outside the measured dose range. The limiting RBE predicted at very low doses per fraction is 20 to 26, whereas at extremely high doses it would be as low as 1.2 to 1.4. This indicates that high RBE values may be seen in a slow turnover tissue after low doses per fraction (within the clinically relevant range) although this may not be evident after larger doses. Such high RBE's arise because of the shape of the underlying X-ray dose-response curve rather than the shape of the neutron curve.     

Cell kinetic changes in the follicular epithelium of pig skin after irradiation with single and fractionated doses of X rays

Changes in the cell kinetics of the follicular epithelium of the pig have been studied after irradiation with single and fractionated doses (30 fractions/39 days) of X rays and the results compared with previously published data for the epidermis. In the follicular epithelium there was an initial degenerative phase, during which the rate of cell depletion was independent of the radiation dose and the mode of administration. Evidence for repopulation was seen between the 14th and 18th days after single doses (15 or 20 Gy) and by the 28th day after the start of irradiation with fractionated doses (52.3-80.0 Gy). However, the degree of cell depletion and the subsequent rate of repopulation were independent of dose. The regenerative phase was characterized by an increased cell proliferation as indicated by an elevation of the labelling index. Islands of cells (colonies), with an appearance similar to cells in the normal follicular epithelium, were seen 18 days after a single dose of 20 Gy and 42 days after the start of fractionated irradiation. When compared with the epidermis, the follicular epithelium exhibited considerably less evidence of damage after both single and fractionated doses of X rays. There was a lower incidence of degenerate cells and reduced levels of cell depletion in the follicular epithelium, suggesting that cells from this region play an important role in the repopulation of the epidermis after high-dose irradiation.     

Late ophthalmological complications after total body irradiation in non-human primates.

PURPOSE: To investigate the long-term effects of total body irradiation (TBI) on the incidence and time course of ocular complications. MATERIALS AND METHODS: Rhesus monkeys treated with TBI photon doses up to 8.5 Gy and proton doses up to 7.5 Gy were studied at intervals up to 25 years post-irradiation. They were compared with control groups with a similar age distribution. Cataract formation and ocular fundus lesions were scored according to a standardized protocol. Fluorescein angiography and histopathology was performed in selected animals. RESULTS: Cataract formation occurred after a latent period of 3-5 years. Significant cataract induction was observed for photon-doses of 8 and 8.5 Gy and beyond 20 years after proton irradiation. The severity of the lesions represents significant impairment of vision and would require cataract surgery if similar results occurred in human bone marrow transplant patients. Fluorescein angiography demonstrated a normal pattern of retinal vessels in 13 out of 14 animals (93%) from the irradiated group and in eight out of nine animals (89%) from the control group. No additional lesions apart from age-related degenerative changes could be demonstrated. Histological evaluation revealed no radiation-associated vasculopathy. CONCLUSIONS: Radiation alone for doses up to 8.5 Gy of photons does not carry a potential risk for fundus pathology, whereas clinically important cataract induction should be anticipated within 5 years after photon doses of 8.0 and 8.5 Gy and proton doses in excess of 2.5 Gy.     

Estimation of doses to heart, coronary arteries, and spinal cord in mediastinal irradiation for Hodgkin's disease.

Early-stage Hodgkin's disease is highly curable with radiotherapy. However, radiotherapy for Hodgkin's disease is not without complications, particularly those related to irradiation of the mediastinum. In attempts to decrease complications, it is important not to compromise the results. To plan such a strategy, one needs to know the doses delivered to various volumes of normal tissues with present techniques. However, such dose-volume data do not exist. Here we demonstrate, with computerized tomography-based dosimetric techniques, such a dose-volume relationship for the heart, coronary arteries, and spinal cord. The doses were determined retrospectively in eight patients. With a prescribed dose of 44 Gy, the volumes of the heart receiving at least 22, 26, 31, 35, 40, or 44 Gy were: 77%, 75%, 70%, 57%, 33%, and 2%, respectively. The average modal doses to the coronary arteries were: anterior interventricular artery, 18.48 Gy; circumflex arterial branch, 37.84 Gy; left coronary artery, 34.76 Gy; and right coronary artery, 36.96 Gy. The average maximum spinal cord dose was 37.25 Gy. A similar prospective documentation of dose-volume relationships and correlation with (functional) long-term complications may be helpful in the development of new strategies for decreasing complications.     

Effect of EGFR-inhibition on the radiation response of oral mucosa: experimental studies in mouse tongue epithelium

The aim was to quantify the effect of selective inhibition of the epidermal growth factor receptor (EGFR) on the radiation response of mouse oral mucosa to daily fractionated irradiation. Irradiation comprised graded single doses of 25 kV X-rays to the lower tongue surface or fractionated doses of 5 x 3 Gy week(-1) (200 kV X-rays) over 1 or 2 weeks, followed by graded local doses, to generate full dose-effect curves. For selective inhibition of EGFR, BIBX1382BS, a tyrosine kinase inhibitor, was administered orally at a dose of 50 mg kg(-1), for the entire overall treatment time. The ED50 (the dose expected to induce ulcer in 50% of the mice) for untreated mucosa was 11.9 +/- 1.2 Gy. Fractionated irradiation administered over 1 or 2 weeks yielded ED50 values for the concluding test irradiation of 6.7 +/- 2.1 and 6.5 +/- 1.9 Gy, respectively. Administration of BIBX1382BS resulted in a non-significant increase of the top-up ED50 to 8.3 +/- 1.6 Gy (p = 0.1197) after 1 week and to 7.6 +/- 1.6 Gy (p = 0.2263) after 2 weeks. EGFR inhibition does not alter the radiation response of oral mucosa to fractionated irradiation or interfere with mucosal repopulation processes. This indicates that the regulation of mucosal repopulation is largely independent of EGFR activation.     

Hyperthermia promotes the incidence of tumours following X-irradiation of the rat cervical cord region.

The cervical region of the rat, including the spinal cord (cervical 5-thoracic 2) was irradiated with single doses of 15-32 Gy 250 kV X-rays. Hyperthermia, at temperatures of 42-, 43- and 44 +/- 0.1 degrees C for 30 min was applied to the cervical vertebral column and immediate adjacent tissues for 5-10 min or 7 h after X-irradiation. Over a period of 18-21 months, animals were followed up to monitor neurological complications occurring as a result of damage to the spinal cord (Sminia et al. 1991). We also noted the development of neoplasms either inside or outside the cervical region. The data on tumour incidence were analysed retrospectively using the actuarial method. Although hyperthermia alone was not carcinogenic, it led to a significant increase of radiation-induced tumours. This increase of radiation carcinogenesis was observed both with hyperthermia applied 5-10 min after X-rays and with an interval of 7 h between X-rays and heat. Cancer induction was highest after the lower radiation doses (16 Gy) combined with high heat doses (30 min 44 degrees C). The latent period for induction of tumours by X-rays was 472 +/- 19 days (mean +/- SEM; n = 24). Latency was significantly shortened by hyperthermia to 404 +/- 34 days (n = 22) if applied 5-10 min after X-rays and to 348 +/- 6 days (n = 33) with an interval of 7 h. Histology revealed that 86% (38/44) of the examined tumours found inside the volume treated with hyperthermia and irradiation were sarcomas. The percentage of animals with a tumour outside the treated volume was almost the same for all treatment groups. Most of these tumours were of the mammary gland type.     

Effect of subsequent acute-dose irradiation on cell survival in vitro following low dose-rate exposures

PURPOSE: Following acute irradiation, excess radiosensitivity is generally seen at doses <1 Gy, a phenomenon termed "low-dose hyper-radiosensitivity" (HRS). A very strong, HRS-like inverse dose-rate effect has also been described following continuous low dose-rate (LDR) irradiation at <30 cGy h(-1). We report on the sequential irradiation of a cell line by such LDR exposures followed by low acute doses, where either treatment individually would elicit a hypersensitive response. The aim was to determine if a prior LDR exposure would remove the HRS normally seen in response to very small acute radiation doses. MATERIALS AND METHODS: T98G human glioma cells were given single continuous LDR exposures of 5-60 cGy h(-1) using a (60)Co gamma-source. At intervals of 0 or 4 h following LDR irradiation, cells were further irradiated with a range of acute doses using 240-kVp X-rays. The response to the combined treatment was assessed using high-precision clonogenic cell survival assays, and the amount of HRS at acute doses <1 Gy was determined. RESULTS: LDR at > or = 60 cGy h(-1) to total doses up to 5 Gy in asynchronously growing cells did not remove HRS in the subsequent acute-dose survival curve. In confluent cultures, subsequent acute-dose HRS was not present after an LDR dose of 5 Gy at either 60 or 30 cGy h(-1), but returned if a 4-h interval was left between LDR and acute-dose irradiation. In confluent cultures, acute-dose HRS remained for LDR treatments at 5 or 10 cGy h(-1) or if the total dose was 2 Gy. Taking all cultures and dose-rates together, the "degree" of acute-dose HRS, as measured by alpha(s), was significantly greater in cells irradiated at LDR to a total dose of 2 than of 5Gy. CONCLUSIONS: Initial LDR exposure can affect a subsequent HRS response. HRS is reduced after LDR exposures at greater dose intensity, but can recover again within 4 h of completion of LDR exposure. This suggests that processes determining increased resistance to small acute doses (removal of HRS) might be governed by the level of repairable DNA lesions.     

Residual radiation-induced damage to the kidney of the pig as assayed by retreatment.

The effect of re-irradiation on the previously irradiated kidney was studied in the Large White female pig. Both kidneys of 14-week-old pigs were initially irradiated with a single dose of 3-7 Gy of 250 kV X-rays. The individual kidney glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and the haematocrit (Hct) were serially measured up to 24 weeks after X-irradiation. Doses of 3 and 5 Gy of X-rays had little effect on the GFR. However, 7 Gy of X-rays caused a marked decline in the GFR up to 12 weeks after irradiation; the GFR then began to recover. A similar pattern of response was seen in the ERPF. In contrast, the Hct was reduced in all pigs 4 weeks after X-irradiation. The extent of the decline and subsequent recovery 24 weeks after irradiation appeared to be related to dose. Twenty-four weeks after X-irradiation both kidneys were re-irradiated with a single dose of 7.9 Gy of 60Co gamma-rays; both kidneys of four age-matched control pigs which had not previously received X-irradiation were similarly treated. Individual kidney GFR, ERPF and Hct were again serially measured up to 24 weeks after gamma-irradiation. Re-irradiation resulted in a significantly greater reduction in the GFR, ERPF and Hct compared with that seen after gamma-irradiation alone. Moreover, the severity of the reduction in the GFR and Hct observed after gamma-irradiation was related, in a dose-dependent manner, to the initial X-ray doses employed. These results indicate that the kidney fails to exhibit complete long-term recovery in function following irradiation. Re-irradiation of the kidney in patients should thus be viewed with extreme caution.     

Effect of subsequent acute-dose irradiation on cell survival in vitro following low dose-rate exposures

Purpose : Following acute irradiation, excess radiosensitivity is generally seen at doses <1 Gy, a phenomenon termed 'low-dose hyper-radiosensitivity' (HRS). A very strong, HRS-like inverse dose-rate effect has also been described following continuous low dose-rate (LDR) irradiation at <30 cGy h -1. We report on the sequential irradiation of a cell line by such LDR exposures followed by low acute doses, where either treatment individually would elicit a hypersensitive response. The aim was to determine if a prior LDR exposure would remove the HRS normally seen in response to very small acute radiation doses. Materials and methods : T98G human glioma cells were given single continuous LDR exposures of 5-60 cGy h -1 using a 60 Co γ-source. At intervals of 0 or 4 h following LDR irradiation, cells were further irradiated with a range of acute doses using 240-kVp X-rays. The response to the combined treatment was assessed using high-precision clonogenic cell survival assays, and the amount of HRS at acute doses <1 Gy was determined. Results : LDR at ≥60 cGy h -1 to total doses up to 5 Gy in asynchronously growing cells did not remove HRS in the subsequent acute-dose survival curve. In confluent cultures, subsequent acute-dose HRS was not present after an LDR dose of 5 Gy at either 60 or 30 cGy h -1, but returned if a 4-h interval was left between LDR and acute-dose irradiation. In confluent cultures, acute-dose HRS remained for LDR treatments at 5 or 10 cGy h -1 or if the total dose was 2 Gy. Taking all cultures and dose-rates together, the 'degree' of acute-dose HRS, as measured by α s, was significantly greater in cells irradiated at LDR to a total dose of 2 than of 5Gy. Conclusions : Initial LDR exposure can affect a subsequent HRS response. HRS is reduced after LDR exposures at greater dose intensity, but can recover again within 4 h of completion of LDR exposure. This suggests that processes determining increased resistance to small acute doses (removal of HRS) might be governed by the level of repairable DNA lesions.     

Functional changes in the pig kidney following irradiation with fractionated doses of fast neutrons (42 MeVd-->Be).

The right kidney of female Large White pigs, approximately 14 weeks old, was irradiated with fractionated doses of fast neutrons (42 MeVd-->Be). The total doses used were 6.6-9.2 Gy. Changes in kidney function, assessed as the functional index (FI, where FI = irradiated kidney function/unirradiated kidney function) or as individual kidney glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), were serially determined up to 104 weeks after irradiation using 99Tcm-DTPA and 131I-hippuran renography. The animals were then euthanized, the kidneys removed and weighed. A dose-dependent reduction in FI was seen within 13 weeks of irradiation. Measuring individual kidney function revealed a hyperaemic response in both irradiated and unirradiated kidney 4 weeks after irradiation. This was followed by a dose-dependent reduction in irradiated kidney GFR and particularly ERPF. The ED50 value for the impairment in ERPF, assessed as the percentage of irradiated kidneys exhibiting a > or = 50% reduction in ERPF, was significantly lower than that for GFR, i.e. 7.20 +/- 0.10 Gy compared with 8.44 +/- 0.07 Gy (p < 0.001). A dose-related reduction in irradiated kidney weight was also observed. These fast neutron-induced changes in renal function and weight are qualitatively similar to those observed following photon irradiation of the pig kidney.     

Low-dose hypersensitivity after fractionated low-dose irradiation in vitro

PURPOSE: It was demonstrated previously that some radioresistant tumour cell lines respond to decreasing single, low radiation doses by becoming increasingly radiosensitive. This paper reports the response of four radioresistant human glioma cell lines to multiple low-dose radiation exposures given at various intervals. Three of the cell lines (T98G, U87, A7) were proven already to show low-dose hyper-radiosensitivity (HRS) after single low doses; the fourth, U373, does not show HRS after acute doses. MATERIALS AND METHODS: Clonogenic cell-survival measurements were made in vitro using the Dynamic Microscopic Image Processing Scanner (DMIPS) or Cell Sorter (CS) following exposure to 240kVp X-rays one or more times. RESULTS: A consistent, time-dependent hypersensitive response to a second, or subsequent, dose was observed in the cell lines that demonstrated HRS. This time-dependent change in radiosensitivity did not occur in the radioresistant cell line that did not show HRS (U373). In one cell line that demonstrated strong HRS, T98G, a similar time-dependent hypersensitive response was also seen when the cells were irradiated whilst held in the G1-phase of the cell cycle. In this same cell line, significantly increased cell kill was demonstrated when three very low doses (0.4 Gy) were given per day, 4 h apart, for 5 days, compared with the same total dose given as once-daily 1.2Gy fractions. CONCLUSIONS: These data demonstrate the possibility that a multipledose per day, low-dose per fraction regimen, termed 'ultrafractionation', could produce increased tumour cell kill in radioresistant tumours compared with the same total dose given as conventional-sized 2 Gy fractions.     

Low-dose hypersensitivity after fractionated low-dose irradiation in vitro

Purpose : It was demonstrated previously that some radioresistant tumour cell lines respond to decreasing single, low radiation doses by becoming increasingly radiosensitive. This paper reports the response of four radioresistant human glioma cell lines to multiple low-dose radiation exposures given at various intervals. Three of the cell lines (T98G, U87, A7) were proven already to show low-dose hyper-radiosensitivity (HRS) after single low doses; the fourth, U373, does not show HRS after acute doses. Materials and methods : Clonogenic cell-survival measurements were made in vitro using the Dynamic Microscopic Image Processing Scanner (DMIPS) or Cell Sorter (CS) following exposure to 240kVp X-rays one or more times. Results : A consistent, time-dependent hypersensitive response to a second, or subsequent, dose was observed in the cell lines that demonstrated HRS. This time-dependent change in radiosensitivity did not occur in the radioresistant cell line that did not show HRS (U373). In one cell line that demonstrated strong HRS, T98G, a similar time-dependent hypersensitive response was also seen when the cells were irradiated whilst held in the G1-phase of the cell cycle. In this same cell line, significantly increased cell kill was demonstrated when three very low doses (0.4 Gy) were given per day, 4 h apart, for 5 days, compared with the same total dose given as once-daily 1.2Gy fractions. Conclusions : These data demonstrate the possibility that a multipledose per day, low-dose per fraction regimen, termed 'ultrafractionation', could produce increased tumour cell kill in radioresistant tumours compared with the same total dose given as conventional-sized 2 Gy fractions.     

白三烯B4受体在寻常型银屑病表皮中的表达

 目的 探讨白三烯B4受体(BLT1和BLT2)在寻常型银屑病患者皮损组织中的表达及与银屑病发病的相关性。方法 选取2014-11至2018-10解放军总医院第三医学中心皮肤科治疗的寻常型银屑病30例患者的石蜡组织标本为银屑病组,另选取整形外科手术切除的正常皮肤30例为对照组。采用链霉素-生物素过氧化物酶(S-P)三步法分别检测两组皮肤表皮中BLT1、BLT2的表达,使用Image-Pro Plus6.0软件系统测量每个视野阳性染色区域的平均光密度(AIOD)值。分析银屑病患者皮损与正常皮肤表皮中BLT1、BLT2的表达强度差异。结果 BLT1、BLT2在寻常型银屑病皮损组织表皮中主要表达于棘层,在正常皮肤组织中主要表达于基底层。与正常皮肤相比,寻常型银屑病患者皮损表皮中BLT1、BLT2表达均明显增强,差异有统计学意义(P<0.05)。结论 白三烯B4受体BLT1、BLT2在寻常型银屑病皮损组织表皮棘层中高表达,提示二者与银屑病的表皮过度增殖有相关性。