title: Reevaluation of the radiosensitizing effects of sanazole and nimorazole in vitro and in vivo.
abstract: Sanazole (AK-2123, 3-nitrotriazole derivative, N1-(3-methoxypropyl)-2-(3-nitro-1 H-1,2,4-triazol-1-yl)acetamide) and nimorazole (5-nitroimidazole derivative, 4-(2-(5-nitro-1H-1-imidazolyl)ethyl)morpholine) have been tested clinically as hypoxic cell radiosensitizers, mainly outside Japan. To determine if these sensitizers deserve clinical investigation in Japan, we reevaluated the radiosensitizing effects of these compounds in vitro and in vivo, in comparison with a fluorinated 2-nitroimidazole derivative KU-2285 (N1-(2-hydroxyethyl)-1,2-difluoro-3-(2-nitro-1 H-1-midazolyl)propanamide). KU-2285 is a known and established radiosensitizer, but is not suitable for clinical studies because of the high cost of synthesis. In vitro, the radiosensitizing effects of the three compounds on SCCVII (squamous cell carcinoma line in C3H mice) tumor cells were examined at 0.5 and 1 mM under aerobic or hypoxic conditions, using a colony assay. In vivo, SCCVII tumors grown subcutaneously in the hind legs of C3H/HeN mice were irradiated with or without prior intraperitoneal administration of 100, 200 or 400 mg/kg of the drugs. Thereafter, tumor growth delay was measured. In vitro, no sensitizing effect was observed under aerobic conditions at 1 mM. Under hypoxic conditions, the sensitizer enhancement ratio (SER) determined at 1% cell survival level for sanazole, nimorazole and KU-2285 was 1.55, 1.45 and 1.95, respectively, at 1 mM, and 1.40, 1.40 and 1.75, respectively, at 0.5 mM. In vivo, all three compounds had significant radiosensitizing effects; their effects appeared to decrease in the order of KU-2285, sanazole, and nimorazole. It was suggested that sanazole may be more suitable for clinical trials than nimorazole.
authors.affiliation: Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Japan. chikao@bg8.so-net.ne.jp
authors.forename: Chikao
authors.initials: C
authors.lastname: Sugie
authors.forename: Yuta
authors.initials: Y
authors.lastname: Shibamoto
authors.forename: Masato
authors.initials: M
authors.lastname: Ito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ogino
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Suzuki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical; D005260:Female; D051379:Mice; D009554:Nimorazole / Q000008:administration & dosage*; D009593:Nitroimidazoles / Q000008:administration & dosage*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D014230:Triazoles; C072690:AK 2123; C069296:KU 2285; D009554:Nimorazole