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- Daşu, Alexandru, et al.
(författare)
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Liquid ionization chamber measurements of dose distributions in small 6 MV photon beams
- 1998
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Ingår i: Physics in Medicine and Biology. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 43:1, s. 21-36
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Tidskriftsartikel (refereegranskat)abstract
- A new liquid ionization chamber (LIC) design optimized for high spatial resolution was used for measurements of dose distributions in radiation fields intended for stereotactic radiosurgery (SRS). This work was mainly focused on the properties of this detector in radiation fields from linear accelerators for clinical radiotherapy (pulsed radiation with dose rates from approximately 0.5 to 5 Gy min-1 and beam diameters down to 8 mm). The narrow beams used in stereotactic radiosurgery require detectors with small sizes in order to provide a good spatial resolution. The LIC is investigated to see whether it can be used as a detector for dose measurements in beams currently used for stereotactic radiosurgery. Its properties are compared with those of silicon diodes. The comparisons include output factor (OF), depth dose and profile measurements in 6 MV photon fields of different sizes. For OF measurements, an NACP air ionization chamber was also used in the comparison. The dependence of the response on the detector orientation in the photon beam is also investigated for the diodes and the LIC. The results suggest that LICs can provide better properties than diodes for measuring dose distributions in narrow photon beams.
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| 2. |
- Daşu, Alexandru, et al.
(författare)
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New insights into factors influencing the clinically relevant oxygen enhancement ratio
- 1998
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Ingår i: Radiotherapy and Oncology. - 0167-8140 .- 1879-0887. ; 46:3, s. 269-277
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: This paper deals with the variations in the oxygen enhancement ratios that could be observed (OER') when comparing oxic and hypoxic cells in different types of fractionated experiments as a consequence of the non-linearity of the underlying cell survival curves. Calculations have been made of the OER' that would be obtained for fractionated irradiations with a series of small doses to allow the comparison of isoeffective doses in oxic and hypoxic conditions. Two styles of fractionated experiment were modelled. In one, the dose per fraction was kept constant in the oxic and hypoxic arms of the experiment, necessitating more fractions in hypoxia to achieve the same level of cell kill. In the other the number of fractions was kept constant and the fraction size was varied to obtain equal levels of damage. The first is the relevant design for the clinic, whereas the second is the design most commonly used in animal studies. MATERIALS AND METHODS: Three models of the survival curve were used to simulate the response of cells to radiation injury, all based on the linear quadratic model, but with various added assumptions. A simple classical LQ model is compared with two models in which the concept of inducible repair is added. In one of these the induction dose for 'switching on' the more resistant response is assumed to be increased in hypoxia and in the other it is assumed to be independent of the oxygen tension. RESULTS: These calculations show a clear and previously unsuspected dependence of the measured OER' on the design of the fractionated experiment. The values obtained in the clinical and animal types of study differ considerably with all three models. The direction and magnitude of that difference depends critically on the assumptions about the fine structure of the survival curve shape. The authors suggest that the inducible repair version with an oxygen-dependent induction dose is probably the most relevant model. Using this, the measured OER' is reduced at doses around 2 Gy for the clinically relevant design of constant sized fractions to the oxic and hypoxic cells. It may even, in certain model assumptions, fall below unity resulting in an increased sensitivity, not resistance, from the hypoxia. CONCLUSIONS: These calculations indicate the urgent need for more knowledge about the fine structure of the low dose region of the survival curves for human tumour cells and especially for comparisons in the presence and absence of oxygen. The extent of the hypersensitivity at very low doses, the trigger dose needed to induce the repair and its oxygen modification may be dominant factors in determining the response of tumour cells to clinically relevant fractionation schedules.
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| 3. |
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| 4. |
- Daşu, Alexandru, et al.
(författare)
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Superfractionation as a potential hypoxic cell radiosensitizer: prediction of an optimum dose per fraction
- 1999
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - 0360-3016 .- 1879-355X. ; 43:5, s. 1083-1094
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: A dose "window of opportunity" has been identified in an earlier modeling study (1) if the inducible repair variant of the LQ model is adopted instead of the pure LQ model, and if all survival curve parameters are equally modified by the presence or absence of oxygen. In this paper we have extended the calculations to consider survival curve parameters from 15 sets of data obtained for cells tested at low doses using clonogenic assays.METHODS AND MATERIALS: A simple computer model has been used to simulate the response of each cell line to various doses per fraction in multifraction schedules, with oxic and hypoxic cells receiving the same fractional dose. We have then used pairs of simulated survival curves to estimate the effective hypoxic protection (OER') as a function of the dose per fraction.RESULTS: The resistance of hypoxic cells is reduced by using smaller doses per fraction than 2 Gy in all these fractionated clinical simulations, whether using a simple LQ model, or the more complex LQ/IR model. If there is no inducible repair, the optimum dose is infinitely low. If there is inducible repair, there is an optimum dose per fraction at which hypoxic protection is minimized. This is usually around 0.5 Gy. It depends on the dose needed to induce repair being higher in hypoxia than in oxygen. The OER' may even go below unity, i.e. hypoxic cells may be more sensitive than oxic cells.CONCLUSIONS: If oxic and hypoxic cells are repeatedly exposed to doses of the same magnitude, as occurs in clinical radiotherapy, the observed hypoxic protection varies with the fractional dose. The OER' is predicted to diminish at lower doses in all cell lines. The loss of hypoxic resistance with superfractionation is predicted to be proportional to the capacity of the cells to induce repair, i.e. their intrinsic radioresistance at a dose of 2 Gy.
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| 5. |
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| 6. |
- Denekamp, Juliana, et al.
(författare)
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Hyperfractionation as an effective way of overcoming radioresistance
- 1998
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - 0360-3016 .- 1879-355X. ; 42:4, s. 705-709
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To model the influence of hypoxic radioprotection in fractionated treatments over a range of fraction sizes. To determine whether there is a "therapeutic window" of dose per fraction where hypoxic radioresistance could be reduced, and if so, where it occurs in different cell lines. MATERIALS AND METHODS: A mathematical model has been used to simulate the response of cells to low doses of radiation, in the region of clinical interest. We have used the inducible repair variant of the linear quadratic (LQ) equation, with a hypersensitive region (alphaS) at low doses that gradually transforms to the accepted "resistance" in the shoulder region (alphaR). It contains two new parameters, the ratio alphaS/alphaR, and D(C). We have accepted that the "induction dose" D(C) is modified by anoxia to the same extent as the other parameters. We have initially modeled using theoretical parameters and then checked the conclusions with 14 sets of published experimental data for cell lines investigated for inducible repair. RESULTS: We have computed the clinical hypoxic protection (OER') as a function of dose per fraction in simulations of clinical fractionated schedules. We have identified a therapeutic window in terms of dose per fraction at about 0.5 Gy, where the OER' is minimized, regardless of the precise cell survival curve parameters. The minimum OER' varies from one cell line to another, falling to about 1.0 if alphaS/alphaR = 6-10 and even far below 1.0 if alphaS/alphaR > or = 20. DISCUSSION: Hyperfractionation using 0.5 Gy fractions may therefore be more effective than oxygen mimetic chemical sensitizers, since it could even make some tumor cells more sensitive than oxic normal tissues. The tumor lines that benefit most from this type of sensitization are those with the highest intrinsic oxic radioresistance, i.e. those with high SF2 values.
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| 7. |
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| 8. |
- Denekamp, Juliana, et al.
(författare)
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Inducible repair and the two forms of tumour hypoxia--time for a paradigm shift
- 1999
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 38:7, s. 903-918
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Tidskriftsartikel (refereegranskat)abstract
- Clinical experience shows that there is a therapeutic window between 60 and 70 Gy where many tumours are eradicated, but the function of the adjacent normal tissues is preserved. This implies much more cell kill in the tumour than is acceptable in the normal tissue. An SF2 of 0.5 or lower is needed to account for the eradication of all tumour cells, while an SF2 of 0.8 or higher is needed to explain why these doses are tolerated by normal tissues. No such systematic difference is known between the intrinsic sensitivity of well-oxygenated normal and tumour cells. The presence of radioresistant hypoxic cells in tumours makes it even more difficult to understand the clinical success. However, there is experimental evidence that starved cells lose their repair competence as a result of the depletion of cellular energy charge. MRS studies have shown that low ATP levels are a characteristic feature of solid tumours in rodents and man. In this paper we incorporate the concept of repair incompetence in starving, chronically hypoxic cells. The increased sensitivity of such cells has been derived from an analysis of mammalian cell lines showing inducible repair. It is proportional to the SF2 and highest in resistant cells. The distinction between acutely hypoxic radioresistant cells and chronically hypoxic radiosensitive cells provides the key to the realistic modelling of successful radiotherapy. It also opens new conceptual approaches to radiotherapy. We conclude that it is essential to distinguish between these two kinds of hypoxic cells in predictive assays and models.
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| 9. |
- Denekamp, Juliana, et al.
(författare)
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Vasculature and microenvironmental gradients: the missing links in novel approaches to cancer therapy?
- 1998
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Ingår i: Advances in Enzyme Regulation. - 0065-2571 .- 1873-2437. ; 38:1, s. 281-299
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Tidskriftsartikel (refereegranskat)abstract
- This paper illustrates how the concept of the malignant cell per se as the prime and only target in cancer therapy may be erroneous. The micro-vasculature evoked to satisfy nutritional requirements of solid tumors, and the inadequacy of this nutrition for all tumor cells, provide novel targeting concepts. The vascular architecture and the microenvironmental gradients (VAMP) will differ from one tumor to another and may determine whether current therapies succeed or fail. Many agents have a different toxicity or mode of action at the pathophysiological oxygen tensions that prevail in solid tumors. This warrants more attention. The hypoxic cell or the immature proliferating endothelial cell may provide tumor specificity that is more general than, and greater than, that conferred by the process of malignant transformation. The poor vasculature of solid tumors is often regarded as a problem by the oncologist. It limits the access of cytotoxic drugs, monoclonal antibodies, cytokines, etc. It also leads to hypoxic radioresistance because of diffusion limited chronic hypoxia and perfusion limited intermittent hypoxia, resulting from transient vessel closure. However, it can also be seen as a potential target, since prolonged vessel occlusion can lead to an avalanche of cell death. Strategies to prevent further expansion of the vascular network (anti-angiogenesis) should stabilize tumors and prevent further growth. Vascular targeting, aiming to damage the microvascular function and cause occlusion, can lead to extensive cell death. The target may relate to the excessive proliferation of endothelial cells in tumors or to abnormal functional aspects, such as altered cell shape (influencing permeability) adhesiveness to leukocytes or steps in the coagulation cascade. These microvascular features and microenvironmental gradients, and the phenotypic consequences of them, have been relatively neglected. The altered milieu and inadequate neovasculature is a common feature of all types of solid tumor, whereas the genetic changes that can give rise to a malignancy are very variable, from tumor site to site and even within a site from individual to individual. It seems, therefore, that therapies that could be of widespread general applicability might more easily be found from the micro-environmental or anti-vascular approaches than from gene therapy targeted at specific oncogenes. This approach will require cross fertilisation between scientists from quite disparate backgrounds, whose paths seldom cross, and who may not read, or even scan, each other's literature. If the endothelium or the low oxygen tension in subsets of tumor cells are the key to successful cancer treatment in mice, there are considerable implications for screening methods in vitro and for predictive and prognostic tests made on homogenized tumor samples.
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