RSR13, an allosteric effector of haemoglobin, and carbogen radiosensitize FSAII and SCCVII tumours in C3H mice

Pre-clinical evaluation has demonstrated that 2-[4-(((3,5-dimethylanilino)carbonyl)methyl)phenoxy]-2-methylpropionic acid (RSR13) acts as an allosteric effector of haemoglobin (Hb). RSR13 binding to Hb results in decreased haemoglobin–oxygen (Hb–O(2)) affinity, improved tumour oxygenation, and enhanced radiation-induced cell killing in several experimental tumour systems. In the present work, ex vivo clonogenic survival analyses are applied in two murine tumour systems to characterize the relationship between the magnitude of decrease in Hb–O(2) affinity and radiosensitization, the influence of inspired pO(2) upon this effect, and the efficacy of combining RSR13 and radiation during a course of repeated radiation exposures. For FSaII tumours in C3H mice breathing air, 100 mg kg(−1) RSR13 administered intraperitoneally produced an enhancement ratio (ER) of 1.3, but there was marked desensitization at a RSR13 dose of 300 mg kg(−1) (ER 0.6). The most likely reason for the increased radioresistance was insufficient oxygen loading of Hb in the pulmonary circulation due to reduced haemoglobin–oxygen affinity because carbogen breathing combined with 300 mg kg(−1) RSR13 reversed the effect and produced an ER of 1.8. In SCCVII tumours in C3H mice irradiated with eight fractions of 2.5 Gy over 4 days, the surviving fraction was reduced to 58–67% of control values when RSR13 was combined with radiation on days 1 and 2, days 3 and 4, or days 1–4. These results confirm that combining RSR13 and irradiation within a fractionated course of clinically relevant low-dose exposures provides significant radiosensitization. Additional preclinical experimentation is needed to define better the optimum dose-scheduling conditions for clinical applications. 1999 Cancer Research Campaign