Radiosensitization with normobaric oxygen and carbogen

Abstract

Although hypoxia is a cause of failure in clinical radiotherapy, the outcome of clinical trials with chemical radiosensitizers, such as misonidazole, has been disappointing [7,8]. Doselimiting toxicity restricts the drug dose per fraction, so that the intratumour concentrations achieved are far lower than those required for detecting a radiosensitizing effect [3]. Therefore, there is a need to identify hypoxic cell radiosensitizers which are non-toxic and effective in fractionated radiotherapy. Recent studies done with low radiation doses per fraction and clinically relevant fractionation regimes have shown, in a mouse mammary carcinoma, that normobaric 100% oxygen is an effective sensitizer [34]. Enhancement ratios (ER) * of 1.45 and 1.3 (at the TCDs0 level, i.e. the dose required to locally control 50% of tumours) were obtained for oxygen with 30 fraction given in an overall time of 6 weeks or 36 fractions in 12 days (Fig. 1). These relatively small enhancement ratios can be translated into a considerable practical gain e.g. by increasing the oxygen concentration from 21 to 100%, tumour control was increased from 0 to 80% (Fig. 1 panel c). A similar gain could be obtained in human tumours where hypoxia limits the response to treatment. Very recently, Gatenby et al. [12] have shown a remarkable and significant correlation between the degree of response to radiotherapy in metastases of the head and neck region and levels of oxygenation within these tumours. Previous studies done in a whole variety of rodent tumours, albeit with fewer fractions, also have shown significant increases in radiosensitivity for either oxygen or carbogen (a mixture of 95% 02 + 5% CO2) [10,15,18,21,32,33,37,40]. Table I and Fig. 2 summarize the ERs for oxygen and carbogen obtained by several investigators using fractionated treatments. Provided an adequate pre-irradiation breathing time (PIBT) is used, ERs in general lie between 1.3 and 1.6 for carbogen and between 1.3 and 1.45 for oxygen. The degree of sensitization achieved with normobaric gases in fractionated regimes is therefore much greater than that seen in almost all animal tumours and human tumour xenografts, with the radiosensitizer misonidazole [6,16,26,31]. Normobaric gases enhance radiosensitivity by increasing the partial pressure of oxygen (pO2) within tumours. The intracapillary saturation of haemoglobin with oxygen can be significantly enhanced in rat tumours by the administration of pure oxygen either under normoor hyperbaric conditions [28]. Improved tumour oxygenation results from increases in the amount of dissolved oxygen and by raising the systemic blood pressure [4,25]. Furthermore, carbogen enhances tumour blood flow and shifts the haemoglobin dissociation curve to the right, thus depressing the affinity of haemoglobin for oxygen [25]. Consequently, carbogen should be a more effective sensitizer than oxygen. Using a fluorescent immunologically labelled 2-nitroimidazole stain for detecting hypoxic cells, recently developed in our laboratory by Hodgkiss and collaborators [17], carbogen decreased the proportion of hypoxic cells in CaNT tumours to a greater extent than oxygen. Hypoxic fractions of 19.0 _ 1.6, 9.4 _+ 2.7 and 2.9 + 1.5% were determined for air, oxygen and carbogen, respectively [33]. These results are in agreement with the slightly higher ERs obtained with carbogen, in this same tumour model, using a local control and regrowth delay assay (Fig. 2, panel b and reference 33). However, the higher Ps0 values (i.e. the oxygen concentration at which 50% of the haemoglobin is saturated with oxygen) for rodent haemoglobin compared with that of humans [13]