title: Comparison of in vivo efficacy of hypoxic cytotoxin tirapazamine and hypoxic cell radiosensitizer KU-2285 in combination with single and fractionated irradiation.
abstract: Development of strategies to eradicate radioresistant hypoxic cells would be of great benefit for clinical radiotherapy. In the present study, the in vivo effects of a promising hypoxic cytotoxin, tirapazamine (3-amino-1,2,4-benzotriazine 1,4-di-N-oxide), were examined in comparison with those of KU-2285, one of the best hypoxic cell radiosensitizers, in combination with both single and fractionated irradiation. The tumor response was assessed by the standard in vivo-in vitro clonogenic 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 tirapazamine was more effective for SCCVII tumors with acutely hypoxic cells, while KU-2285 was more effective for EMT-6/KU tumors predominantly with chronically hypoxic cells. In fractionated irradiation regimens (4 fractions of 5 Gy at 12 h intervals), tirapazamine showed more marked combined effects at 10 and 20 mg/kg than KU2285 at 100-200 mg/kg in both SCCVII and EMT-6/KU tumors. We concluded that the effectiveness of KU-2285 and tirapazamine was correlated with the nature of tumor hypoxia with single-dose irradiation, whereas tirapazamine appeared more potent than KU-2285 with fractionated irradiation. These findings suggest the potential usefulness of tirapazamine in clinical fractionated radiotherapy.
authors.affiliation: Department of Radiology, Faculty of Medicine, Kyoto University.
authors.forename: T
authors.initials: T
authors.lastname: Shibata
authors.forename: Y
authors.initials: Y
authors.lastname: Shibamoto
authors.forename: K
authors.initials: K
authors.lastname: Sasai
authors.forename: N
authors.initials: N
authors.lastname: Oya
authors.forename: R
authors.initials: R
authors.lastname: Murata
authors.forename: T
authors.initials: T
authors.lastname: Takagi
authors.forename: M
authors.initials: M
authors.lastname: Hiraoka
authors.forename: M
authors.initials: M
authors.lastname: Abe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000532:radiotherapy*; D009593:Nitroimidazoles / Q000494:pharmacology*; D011879:Radiotherapy Dosage; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D014227:Triazines; C069296:KU 2285; D000077704:Tirapazamine