Wouters, B. G. & Brown, J. M. Cells at intermediate oxygen levels can be more important than the hypoxic fraction in determining tumor response to fractionated radiotherapy. Radiat. Res. 147, 541-550

Department of Radiation Oncology, Stanford University School of Medicine, California 94305-5468, USA.
Radiation Research (Impact Factor: 2.91). 06/1997; 147(5):541-50. DOI: 10.2307/3579620
Source: PubMed


The presence of hypoxic cells in human tumors is thought to be one of the principal reasons for the failure of radiation therapy. Intensive laboratory and clinical efforts to overcome tumor hypoxia have focused on oxygenating, radiosensitizing or killing the maximally radioresistant fraction of tumor cells. This "hypoxic fraction" dominates the single-dose radiation response, irrespective of the oxygenation status of the remainder of the tumor cell population. However, at doses that are typical of those delivered in a daily radiotherapy protocol, we show that the tumor response is highly dependent upon the cells at oxygen levels intermediate between fully oxygenated and hypoxic (0.5-20 mm Hg). For most tumors, these cells are more important than the radiobiologically hypoxic cells in determining treatment outcome after 30 fractions of 2 Gy. We also show that under conditions of diffusion-limited hypoxia, the impact of full reoxygenation between fractions is much smaller than previously realized. Together, the results imply that tumor hypoxia plays a more significant role in determining the outcome of fractionated radiotherapy than previous measurements and assumptions of hypoxic fractions have indicated. Therefore, the concept of a hypoxic fraction in human tumors is less meaningful when pertaining to a fractionated radiotherapy regimen, and should not be expected to be useful for predicting tumor responses in the clinic. This implies the need to characterize tumor oxygenation in a manner that reflects the true oxygenation status of all the tumor cells, not just the ones most refractory to the effects of ionizing radiation. Furthermore, effective therapeutic agents must have the ability to specifically sensitize or kill those cells at intermediate levels of oxygen in addition to the radiobiologically hypoxic cells.

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    • "This boosting fraction is referred to as the oxygen enhancement ratio (OER). Half maximum radio-sensitivity occurs somewhere around an oxygen partial pressure of 3 mmHg, with maximum OER typically achieved at partial pressures p 20 mmHg, > with subsequent increases not significantly modifying the curve [1] [6]. Experiments performed in cells, yeast and bacteria conform to the same general OER curve, which rises and quickly saturates [1], obeying a roughly hyperbolic relationship with oxygen tension [1] [7] [8]. "
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    ABSTRACT: The presence of oxygen in tumours has substantial impact on treatment outcome; relative to anoxic regions, well-oxygenated cells respond better to radiotherapy by a factor 2.5–3. This increased radio-response is known as the oxygen enhancement ratio. The oxygen effect is most commonly explained by the oxygen fixation hypothesis, which postulates that radical-induced DNA damage can be permanently 'fixed' by molecular oxygen, rendering DNA damage irreparable. While this oxygen effect is important in both existing therapy and for future modalities such a radiation dose-painting, the majority of existing mathematical models for oxygen enhancement are empirical rather than based on the underlying physics and radiochemistry. Here we propose a model of oxygen-enhanced damage from physical first principles, investigating factors that might influence the cell kill. This is fitted to a range of experimental oxygen curves from literature and shown to describe them well, yielding a single robust term for oxygen interaction obtained. The model also reveals a small thermal dependency exists but that this is unlikely to be exploitable.
    Full-text · Article · Dec 2015
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    • "Many tumors must adapt to relatively low levels of oxygen (Brown 2007, McKeown 2014), a state that can increase resistance to radiotherapy (Gray et al 1953, Hodgkiss et al 1987). In fact, cells at intermediate oxygen states are of the most concern as they are the most important to therapy resistance dynamics (Wouters and Brown 1997). It is also these intermediate states of oxygen that would coincide with intermediate states of glucose availability where the glycolytic oscillator is expected to occur locally. "
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    ABSTRACT: Tumor acute hypoxia has a dynamic component that is also, at least partially, coherent. Using blood oxygen level dependent magnetic resonance imaging, we observed coherent oscillations in hemoglobin saturation dynamics in cell line xenograft models of head and neck squamous cell carcinoma. We posit a well-established biochemical nonlinear oscillatory mechanism called the glycolytic oscillator as a potential cause of the coherent oscillations in tumors. These data suggest that metabolic changes within individual tumor cells may affect the local tumor microenvironment including oxygen availability and therefore radiosensitivity. These individual cells can synchronize the oscillations in patches of similar intermediate glucose levels. These alterations have potentially important implications for radiation therapy and are a potential target for optimizing the cancer response to radiation.
    Full-text · Article · Nov 2015 · Physics in Medicine and Biology
    • "Alternative modeling approaches were based on ODE (Ordinary Differential Equation) and PDE (Partial Differential Equation) and included dead/inactivated cell kinetics [14], the effects of oxygenation [1], [3], [15], [16], and different microenvironment conditions [12]. Early studies reported that the radioresponsiveness of homogenous cell lines can sensibly vary as a function of many factors, such as cancer volume size, level of oxygenation, vascularization, and delivered dose [17], [18], with a general consensus that the larger the volume size is, the smaller the cell killing rate is expected to be, due to larger hypoxia effects [19]. Furthermore, it was shown that reoxygenation may occur because of tumor shrinkage, decreased oxygen consumption, and increased perfusion [15],[16]. "
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    ABSTRACT: This paper describes a patient-specific mathematical model to predict the evolution of uterine cervical tumors at a macroscopic scale, during fractionated external radiotherapy. The model provides estimates of tumor re-growth and dead-cell reabsorption, incorporating the interplay between tumor regression rate and radiosensitivity, as a function of the tumor oxygenation level. Model parameters were estimated by minimizing the difference between predicted and measured tumor volumes, these latter being obtained from a set of 154 serial cone-beam computed tomography (CBCT) scans acquired on 16 patients along the course of the therapy. The model stratified patients according to two different estimated dynamics of dead-cell removal and to the predicted initial value of the tumor oxygenation. The comparison with a simpler model demonstrated an improvement in fitting properties of this approach (fitting error average value <5%, p<0.01), especially in case of tumor late responses, which can hardly be handled by models entailing a constant radiosensitivity, failing to model changes from initial severe hypoxia to aerobic conditions during the treatment course. The model predictive capabilities suggest the need of clustering patients accounting for cancer cell-line, tumor staging, as well as microenvironment conditions (e.g. oxygenation level).
    No preview · Article · Jan 2015 · IEEE Journal of Biomedical and Health Informatics
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