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)c arbonyl)methyl)phenoxy]-2-methylpropionic acid (RSR13) acts as an allosteri c effector of haemoglobin (Hb). RSR13 binding to Hb results in decreased ha emoglobin-oxygen (Hb-O-2) affinity, improved tumour oxygenation, and enhanc ed radiation-induced cell killing in several experimental tumour systems. I n the present work, ex vivo clonogenic survival analyses are applied in two murine tumour systems to characterize the relationship between the magnitu de 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 ra diation during a course of repeated radiation exposures. For FSall tumours in C3H mice breathing air, 100 mg kg(-1) RSR13 administered intraperitoneal ly produced an enhancement ratio (ER) of 1.3, but there was marked desensit ization at a RSR13 dose of 300 mg kg(-1) (ER 0.6). The most likely reason f or the increased radioresistance was insufficient oxygen loading of Hb in t he pulmonary circulation due to reduced haemoglobin-oxygen affinity because carbogen breathing combined with 300 mg kg(-1) RSR13 reversed the effect a nd produced an ER of 1.8. In SCGVII tumours in C3H mice irradiated with eig ht fractions of 2.5 Gy over 4 days. the surviving fraction was reduced to 5 8-67% of control values when RSR13 was combined with radiation on days 1 an d 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-dos e exposures provides significant radiosensitization. Additional preclinical experimentation is needed to define better the optimum dose-scheduling con ditions for clinical applications.