Protection of Pig Epidermis against Radiation-induced Damage by the Infusion of BW12C

Summary

BW12C, which was developed as an agent for the treatment of sickle cell anaemia, increases the binding of oxygen to haemoglobin and hence reduces the availability of oxygen to tissues. Due to these changes in oxygen availability BW12C could act as a protector against radiation-induced injury to normal tissues. In this study the potential value of BW12C, as a radioprotector, was studied in the irradiated epidermis of the pig. The infusion of BW12C caused an instant left shift of the oxygen dissociation curve, an effect that lasted for ∼1·5 h. This left shift in the oxygen dissociation curves increased with increasing dose of the drug. There appeared to be no long-term systemic effects produced by doses of 20–100 mg/kg of BW12C. In the first 90 min after the infusion of BW12C skin fields were irradiated with single doses of β-rays from strontium-90 plaques. The incidence of moist desquamation was used as an endpoint for assessing the severity of the radiation response. With animals breathing ∼70% oxygen in the anaesthetic gas mixture, the ED₅₀ values for moist desquamation were 30–31 Gy after a dose of 30 and 50 mg/kg, and 37–38 Gy for 75 and 100 mg/kg doses of BW12C. These ED₅₀ values were significantly higher than the value of 27·3 Gy for radiation alone. This indicated dose modification factors (DMF) with mean values of ∼1·13 and ∼1·40 for irradiation following the infusion of low (30–50 mg/kg) and high (75–100 mg/kg) doses of the drug, respectively. With the animals breathing air (∼21% of oxygen) in the 2% halothane anaesthesia gas mixture, irradiation in the presence of 30 and 50 mg/kg of BW12C resulted in ED₅₀ values of ∼39 Gy for moist desquamation, which was significantly higher than the value of 31·2 Gy for radiation alone. Surprisingly, a higher dose of 75 mg/kg of BW12C resulted in a lower ED₅₀ value for moist desquamation of 34·38 Gy. Irradiation in the presence of a dose of 100 mg/kg of BW12C produced an ED₅₀ value which was not significantly different from that for radiation alone. In the situation where animals were breathing air (∼21% oxygen) during irradiation a DMF of 1·14 was obtained for irradiation alone, when the results were compared with those for irradiation alone with ∼70% oxygen in the anaesthetic gas mixture. When this ‘air component’ is taken into account DMF values of ∼1·3 were obtained for 30 and 50 mg/kg of BW12C, whereas for 75 and 100 mg/kg of BW12C this was reduced to 1·11 and 1·0, respectively. These modifications in the sensitivity of the epidermis for irradiation in the presence of various doses of BW12C were not uniform over the flank skin of the pig. For all doses of BW12C used, the skin fields positioned dorsally on the flank always showed a reduced radiosensitivy when compared with the ventrally positioned skin sites. This suggested a better physiological compensation for the effect produced by the drug in the ventral area of the flank skin. A similar variation in the radiosensitivity over the flank was noted for radiation alone when pigs were breathing air (∼21% oxygen) in the anaesthetic gas mixture. Only when animals were breathing ∼70% oxygen in the anaesthetic gas mixture was the radiosensitivity of the skin uniform over the whole flank.