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A system for culturing sheep thyroid cells in vitro is described. The properties of the cultures may be manipulated so that they preserve in vitro the follicular architecture typical of the thyroid, or so that they undertake cellular proliferation. The cultured cells also undertake iodide metabolism. These growth and differentiation characteristics can be preserved for at least three weeks, which is sufficient time for assay of many radiobiological end-points.
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PURPOSE: The ASTRO Joint Working Group on Radiobiology Teaching, a committee composed of members having affiliations with several national radiation oncology and biology-related societies and organizations, commissioned a survey designed to address issues of manpower, curriculum standardization, and instructor feedback as they relate to resident training in radiation biology. METHODS AND MATERIALS: Radiation biology instructors at U.S. radiation oncology training programs were identified and asked to respond to a comprehensive electronic questionnaire dealing with instructor educational background, radiation biology course content, and sources of feedback with respect to curriculum planning and resident performance on standardized radiation biology examinations. RESULTS: Eighty-five radiation biology instructors were identified, representing 73 radiation oncology residency training programs. A total of 52 analyzable responses to the questionnaire were received, corresponding to a response rate of 61.2%. CONCLUSION: There is a decreasing supply of instructors qualified to teach classic, and to some extent, clinical, radiobiology to radiation oncology residents. Additionally, those instructors with classic training in radiobiology are less likely to be comfortable teaching cancer molecular biology or other topics in cancer biology. Thus, a gap exists in teaching the whole complement of cancer and radiobiology curricula, particularly in those programs in which the sole responsibility for teaching falls to one faculty member (50% of training programs are in this category). On average, the percentage of total teaching time devoted to classic radiobiology (50%), clinical radiobiology (30%), and molecular and cancer biology (20%) is appropriate, relative to the current makeup of the board examination. Nevertheless large variability exists between training programs with respect to the total number of contact hours per complete radiobiology course (ranging from approximately 10 to >50 h). A number of lecture topics, particularly in clinical radiobiology, are covered by fewer than 60% of training programs. A sizeable minority of radiation biology instructors are dissatisfied with the feedback they receive with respect to both course content and the performance of their residents on standardized radiobiology examinations administered by the American College of Radiology and/or the American Board of Radiology.
PURPOSE: Tumour hypoxia causes resistance to treatment and may promote the development of metastatic disease. The mean fraction of radiobiologically hypoxic cells has been determined for a large number of tumour cell lines, but quantitative information on intertumour heterogeneity in radiobiological hypoxia is sparse, and it is not known whether radiobiological hypoxia is mainly either chronic or acute in nature. The purpose of the work reported here was (1) to determine the fraction of radiobiologically hypoxic cells in individual tumours and (2) to differentiate quantitatively between chronic and acute hypoxia. MATERIALS AND METHODS: Four human melanoma xenograft lines (A-07, D-12, R-18, U-25) were included. A radiobiological assay based on the paired survival curve method was established to measure the fraction of radiobiologically hypoxic cells. An immunohistochemical assay using the hypoxia marker pimonidazole was developed to determine the fraction of chronically hypoxic cells. The fraction of acutely hypoxic cells was estimated from the fraction of radiobiologically hypoxic cells and the fraction of chronically hypoxic cells. RESULTS: The fractions of radiobiologically hypoxic cells were in the ranges of 1-49% (A-07), 10-69% (D-12), 22-87% (R-18) and 23 85% (U-25); the fractions of chronically hypoxic cells were in the ranges of 0-15% (A-07), 5-25% (D-12), 4-17% (R-18) and 9-25% (U-25); the fractions of acutely hypoxic cells were in the ranges of 1-47% (A-07), 1-57% (D-12), 9-80% (R-18) and 5-69% (U-25). The fraction of acutely hypoxic cells was higher than the fraction of chronically hypoxic cells in most A-07, R-18 and U-25 tumours. The fraction of chronically hypoxic cells was higher than the fraction of acutely hypoxic cells in 16 of 25 D-12 tumours. CONCLUSION: This study indicates that acute hypoxia in tumours is a far more serious problem than chronic hypoxia and, consequently, it may be beneficial to focus on acute hypoxia rather than chronic hypoxia when searching for clinically useful predictive assays of hypoxia-induced radiation resistance and malignant progression and for methods to overcome treatment resistance caused by hypoxia.
Radiotherapy treatment plan evaluation relies on an implicit estimation of the tumor control probability (TCP) and normal tissue complication probability (NTCP) arising from a given dose distribution. A potential application of radiobiological modeling to radiotherapy is the ranking of treatment plans via a more explicit determination of TCP and NTCP values. Although the limited predictive capabilities of current radiobiological models prevent their use as a primary evaluative tool, radiobiological modeling predictions may still be a valuable complement to clinical experience. A convenient computational module has been developed for estimating the TCP and the NTCP arising from a dose distribution calculated by a treatment planning system, and characterized by differential (frequency) dose-volume histograms (DDVHs). The radiobiological models included in the module are sigmoidal dose response and Critical Volume NTCP models, a Poisson TCP model, and a TCP model incorporating radiobiological parameters describing linear-quadratic cell kill and repopulation. A number of sets of parameter values for the different models have been gathered in databases. The estimated parameters characterize the radiation response of several different normal tissues and tumor types. The system also allows input and storage of parameters by the user, which is particularly useful because of the rapidly increasing number of parameter estimates available in the literature. Potential applications of the system include the following: comparing radiobiological predictions of outcome for different treatment plans or types of treatment; comparing the number of observed outcomes for a cohort of patient DVHs to the predicted number of outcomes based on different models/parameter sets; and testing of the sensitivity of model predictions to uncertainties in the parameter values. The module thus helps to amalgamate and make more accessible current radiobiological modeling knowledge, and may serve as a useful aid in the prospective and retrospective analysis of radiotherapy treatment plans.
Fluoromisonidazole [1-(2-nitroimidazolyl)-2-hydroxy-3-fluoropropane, FMISO] shows promise as a hypoxia imaging agent: it binds preferentially to anoxic cells in monolayers in vitro and accumulates in radiobiologically hypoxic tumors in vivo. The multicellular spheroid model was used to determine if the radiobiologically hypoxic fraction could be predicted from data on the uptake of FMISO. Chinese hamster V79-171b spheroids approximately 500 microns in diameter were exposed to 50 mM [3H]FMISO for 1 to 6 h under aerobic (5% CO2 in air), hypoxic (5% CO2, 5% O2, in N2) or anoxic (5% CO2 in N2) conditions and FMISO uptake was measured. Uptake in anoxic spheroids was similar to that in anoxic cell monolayers, while there was virtually no uptake in aerobic spheroids. A mathematical model was developed to calculate the radiobiologically hypoxic fraction in the hypoxic spheroids from the data on FMISO uptake. A radiobiologically hypoxic fraction of 15% was obtained, consistent with that determined from radiation survival assays (17%) and measurements of oxygen consumption (22%). We conclude that the rate of FMISO uptake in V79-171b spheroids correlates with the radiobiologically hypoxic fraction. Furthermore, the radiobiologically hypoxic fraction can be calculated from data on FMISO uptake if the dependence of FMISO uptake on oxygen concentration is known for a given tumor cell type.
The use of molecular medicine is now merging into clinical practice with the advent of molecular targeting agents, molecular pathology and molecular imaging for both diagnosis and treatment response. Radiation oncologists must therefore gain expertise in utilizing this information to drive new treatment protocols. Recognizing the importance of this issue, the Canadian Association of Radiation Oncologists (CARO) charged a Task Force in Translational Radiobiology to: (1) critically assess training programs and research infrastructure in relation to current and future translational radiobiology requirements; and (2) make specific recommendations to accelerate the implementation of translational science into day-to-day practice. Selected Task Force recommendations included the principle that universities and departmental Chairs increase the opportunities for academic promotion, funding, and tenure track positions of radiobiologists and translational radiation oncologists. The dedication of 4 to 5 national centers as translational 'hubs', can serve as an interface between clinicians, clinical specimens and radiobiological sciences within the context of correlative clinical trials. The model of the clinician-scientist was encouraged as an important adjunct to good clinical care to be associated with strong enticement, training and mentoring programs and 75%-protected research time. Finally, an integrated model of radiobiological training programs and mutual continuing education between clinicians and basic scientists can be facilitated through a new national radiobiology meeting sponsored by CARO. These recommendations have been accepted by the national radiation oncology membership. Such a framework may serve useful for national programs wishing to develop rapid conduits from the lab to the clinic as a means of integrating molecular biology and the day-to-day practice of radiation oncology.
Since the beg inning of manned space flight the potentially unique radiobiological properties of the heavy ions of the cosmic radiation had been, apart from possible interactions of radiation effects with biological effects of weightlessness, of major concern with respect to the assessment of radiation hazards in manned space flight. Radiobiological findings obtained from space flight experiments and ground based experiments with densely ionizing radiation are discussed, which suggest qualitative differences between the radiobiological mechanisms of sparsely ionizing and densely ionizing radiation. These findings comprise the observation of a long lateral range of radiobiological effectiveness around tracks of single heavy ions, the observation of micro lesions induced in biological targets by the penetration of heavy ions, the nonadditivity of radiobiological effects from sparsely and densely ionizing radiation, the different kinetics for the expression of late effects induced by sparsely or densely ionizing radiation, and the observation of a reversed dose rate effect for early and late effects induced by densely ionizing radiation. These findings bear on the radiation protection standards to be installed for a general public in manned space flight and on the design of experiments, which intend to contribute to their specification.
BACKGROUND AND PURPOSE: Recent analysis of morbidity for patients treated with the continuous hyperfractionated accelerated radiotherapy (CHART) regimen demonstrates that repair half-times for late-reacting normal tissue cells are of the order of 4-5 h, which is considerably longer than previously believed. This would reduce repair of these tissue cells during a course of low-dose rate (LDR) brachytherapy, but have no effect at high-dose-rate (HDR), where there is no repair during, and full repair between fractions, regardless of repair half-time. The effect this has upon radiobiologic comparison of LDR and HDR is the topic of this paper. METHODS AND MATERIALS: The linear-quadratic (L-Q) model is used to compare late-effect biologically effective doses (BEDs) of LDR and HDR, for constant BED (tumor). The effects of dose rate (for LDR), fractionation (for HDR), and geometrical sparing of normal tissues are all considered. Repair half-times observed in the CHART study are used to investigate the potential impact of long repair times on the comparison of LDR and HDR. RESULTS: It is demonstrated that, for a repair half-time of 1.5 h for tumor cells, if the half-time for repair of late-reacting normal tissue cells exceeds about 2.5 h, LDR becomes radiobiologically inferior to HDR. Even with the least HDR-favorable combinations of parameters, HDR at over about 5 Gy/fraction ought to be radiobiologically superior to LDR at 0.5 Gy/h, so long as the time between HDR fractions is long compared to the repair half time. It is also shown that any geometrical sparing of normal tissues will benefit HDR more than LDR. CONCLUSION: The previously held belief that LDR must be inherently superior radiobiologically to HDR is wrong if the long repair times demonstrated in the recent CHART study are applicable to other late-reacting normal tissues. This could explain why HDR has been so successful in clinical practice, especially for the treatment of cervical cancer, despite previous convictions of radiobiologic inferiority of this modality.
The meeting was reviewed and summarised by Professor Herman Suit. He judged that the potential clinical gains from research in radiobiology were very great and likely to translate to improved cancer treatment in the near future. He was highly complimentary about the contribution of UK research in radiobiology and he indicated that this viewpoint was held widely in the United States, Europe and Japan. Radiobiological research was the basis for major clinical trials in radiotherapy undertaken by trial groups in all these countries. He felt that major contributions to current practice in radiotherapy had been the definition of dose response, the rationale for the use of radiotherapy against slowly responding tumours, and the understanding of repair differentials and of clonal proliferation in the design of clinical fractionation trials, leading to clear demonstration of benefit for altered fractionation in the treatment of head and neck cancer and in the treatment of bladder cancer. An important goal of research should be the development of predictive testing for radiation response employing multiple predictive tests of radiation sensitivity (survival at 2 Gy), cellular proliferation (potential doubling time) and identification of hypoxic cells, together with physiological parameters such as blood flow intratumoral pressure, thiol metabolism and activation and status of repair genes. In terms of improving differential response between tumour and normal tissues, further refinement of dose fractionation patterns would be needed, but also research should continue on the modification of response using drug/radiation protocols, targeting techniques, growth factors and other biological response modifiers to support normal tissues, and modulation of DNA repair. Professor Suit felt that the pace of research in radiobiology was most encouraging for the field of radiotherapy. There was a consensus that support for radiobiology needed to be matched by support for academic radiotherapy if potential research gains were to be translated into advances in treatment. He shared the view expressed by the Committee of Cancer Experts of the EORTC that improvements in cancer cure over the next decade were likely to derive from improvements in radiotherapy.
The magnitude of the fraction of radiobiologically hypoxic cells in tumours is generally believed to reflect the efficiency of the vascular network. Theoretical studies have suggested that the hypoxic fraction might also be influenced by biological properties of the tumour cells. Quantitative experimental results of cell energy metabolism, hypoxia- induced apoptosis, and radiobiological hypoxia are reported here. Human melanoma multicellular spheroids (BEX-c and WIX-c) were used as tumour models to avoid confounding effects of the vascular network. Radiobiological studies showed that the fractions of hypoxic cells in 1000-microM spheroids were 32 +/- 12% (BEX-c) and 2.5 +/- 1.1% (WIX-c). The spheroid hypoxic volume fractions (28 +/- 6% (BEX-c) and 1.4 +/- 7% (WIX-c)), calculated from the rate of oxygen consumption per cell, the cell packing density, and the thickness of the viable rim, were similar to the fractions of radiobiologically hypoxic cells. Large differences between tumours in fraction of hypoxic cells are therefore not necessarily a result of differences in the efficiency of the vascular network. Studies of monolayer cell cultures, performed to identify the biological properties of the BEX-c and WIX-c cells leading to this large difference in fraction of hypoxic cells, gave the following results: (1) WIX-c showed lower cell surviving fractions after exposure to hypoxia than BEX-c, (2) WIX-c showed higher glucose uptake and lactate release rates than BEX-c both under aerobic and hypoxic conditions, and (3) hypoxia induced apoptosis in WIX-c but not in BEX-c. These observations suggested that the difference between BEX-c and WIX-c spheroids in fraction of hypoxic cells resulted partly from differences in cell energy metabolism and partly from a difference in capacity to retain viability under hypoxic stress. The induction of apoptosis by hypoxia was identified as a phenomenon which has an important influence on the magnitude of the fraction of radiobiologically hypoxic cells in multicellular spheroids.
The radiobiological effect of intracellularly localised radionuclides emitting low energy electrons (Auger electrons) has received much attention. Most in vivo studies reported have been performed in the mouse testis. We have investigated the rat testis as an in vivo radiobiological model, with sperm-head survival, testis weight loss and also alteration in the blood plasma hormone levels of FSH and LH as radiobiological endpoints. Validation of the rat testis model was evaluated by using mean absorbed doses of up to 10 Gy from intratesticularly (i.t.) injected (111)In oxine or local X-ray irradiation. Biokinetics of the i.t. injected radionuclide was analysed by scintillation camera imaging and used in the absorbed dose estimation. By the analysis of the autoradiographs, the activity distribution was revealed. Cell fractionation showed (111)In to be mainly associated with the cell nuclei. External irradiations were monitored by thermoluminescence dosimeters. The sperm-head survival was the most sensitive radiobiological parameter correlated to the mean absorbed dose, with a D(37) of 2.3 Gy for (111)In oxine and 1.3 Gy for X rays. The levels of plasma pituitary gonadal hormones FSH and LH were elevated for absorbed doses >7.7 Gy. This investigation shows that the radiobiological model based on the rat testis has several advantages compared with the previously commonly used mouse testis model. The model is appropriate for further investigations of basic phenomena such as radiation geometry, intracellular kinetics and heterogeneity, crucial for an understanding of the biological effect of low-energy electrons.
A methodology for predicting the expected combined stochastic radiobiological effects of sequential exposure to different ionizing radiations is used to arrive at a methodology for predicting the radiobiological effects of simultaneous exposure. Both methodologies require developing additive-damage dose-effect models. Additive-damage dose-effect models are derived assuming (a) each radiation comprised by the combined exposure produces initial damage called critical damage that could lead to the radiobiological effect of interest; (b) doses of different radiations that lead to the same level of radiobiological effect (or risk) can be viewed as producing the same amount of critical damage and being indistinguishable as far as the effects of subsequently administered radiation. Derived dose-effect functions that describe the risk per individual, conditional on radiation dose, are called risk functions. The methodologies allow the use of known radiation-specific risk functions to derive risk functions for combined effects of different radiations. The risk functions for combined exposure to different radiations are called global risk functions. For sequential exposures to different ionizing radiations, the global risk functions derived depend on how individual radiation doses are ordered. Global risk functions can also differ for sequential and simultaneous exposure. The methodologies are used to account for some previously unexplained radiobiological effects of combined exposure to high and low linear-energy-transfer radiations.