COMPARISON OF IN-VIVO EFFICACY OF HYPOXIC CYTOTOXIN TIRAPAZAMINE AND HYPOXIC CELL RADIOSENSITIZER KU-2285 IN COMBINATION WITH SINGLE AND FRACTIONATED-IRRADIATION

Development of strategies td eradicate radioresistant hypoxic cells wo uld be of great benefit for clinical radiotherapy. In the present stud y, the in vivo effects of a promising hypoxic cytotoxin, tirapazamine (3-amino-1,2,4-benzotriazine 1,4-di-N-oxide), were examined in compari son with those of KU-2285, one of the best hypoxic cell radiosensitize rs, in combination with both single and fractionated irradiation. The tumor response was assessed by the standard in vivo-in vitro clonogeni c assay using SCCVII tumors in C3H mice and EMT-6/KU tumors in Balb/c mice with different characteristics of tumor hypoxia. With single-dose irradiation (18 Gy), both tirapazamine and KU-2285 showed significant enhancement of cell killing in a dose-dependent manner, but tirapazam ine was more effective for SCCVII tumors with acutely hypoxic cells, w hile KU-2285 was more effective for EMT-6/KU tumors predominantly with chronically hypoxic cells. In fractionated irradiation regimens (4 fr actions of 5 Gy at 12 h intervals), tirapazamine showed more marked co mbined effects at 10 and 20 mg/kg than KU-2285 at 100-200 mg/kg in bot h SCCVII and EMT-6/KU tumors, We concluded that the effectiveness of K U-2285 and tirapazamine was correlated with the nature of tumor hypoxi a with single-dose irradiation, whereas tirapazamine appeared more pot ent than KU-2285 with fractionated irradiation. These findings suggest the potential usefulness of tirapazamine in clinical fractionated rad iotherapy.