Radiation Dose Dependence of the Sensitization by Oxygen and Oxygen Mimic Sensitizers

Abstract

New and old evidence is discussed which suggests that the oxygen enhancement ratio (OER) is decreased at lower radiation doses as compared with that of higher radiation doses. In addition, there is evidence that cells irradiated in severe hypoxia have an impaired ability to recover from sublethal damage. However, there is also contrary evidence to these observations. Thus the suggestions that oxygen is not strictly a dose modifying agent have been controversial from the very beginning. It is hoped that new experimental undertakings currently performed in many different laboratories will resolve these issues as well as explain the controversy which has lasted more than 25 years in this field of radiobiologic research.The development of the clonogenic technique (36) which facilitates quantitative measurements of cell survival as a function of radiation dose of mammalian cells grown in tissue culture, signifies a milestone in modem radiation biology. In general terms, dose/response curves (logarithm of cell survival S as a function of dose D of ionizing radiation) of aerobic cells have been characterized by, a) an initial shoulder at lower doses and b) nearly exponential cell kill at higher doses, which results in an approximate straight line (Fig. 1). The slope of the straight line is defined by the quantity Do, which represents the dose reducing cell survival by approximately 37 per cent (Ve). Extrapolation of the exponential part of the curve to zero dose gives the 'extrapolation number' n which is a measure of the shoulder. Since a given increment of radiation dose kills fewer cells in the shoulder region than in the exponential region of the survival curve, the shoulder implies a certain protection of the cells at lower radiation doses. The pioneering work of ELKIND & SUTT~N (9), using split-dose experiments, indicated that this protection can be explained by the recovery (repair) of sublethally damaged cells.The fact that hypoxic cells were found in the deficiently vascularized neoplastic tissues stimulat- ed widespread interest of radiation response of hypoxic cells. Despite this interest, a relatively long period of time elapsed between the introduction of the clonogenic techniques is 1956 and the publication of the first report (6) in which this technique was used in studies of survival of hypoxically irradiated mammalian cells. At that time, it was not known that oxygen, which is dissolved in plastic material, would prevent attached cells from becoming hypoxic even in a carefully de-aerated medium (5). Therefore, the cells in the reported experiments were probably not as hypoxic as originally assumed. The Department of Radiation Therapy at Stanford University was among the first institutions in which a systematic investigation of the survival characteristics of cultured mammalian cells was initiated whereby the cells were irradiated under severely hypoxic conditions (45). It was by chance that glass dishes were used instead of plastic dishes to maintain the cells in these studies. Furthermore, alt...

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