title: The influence of hypoxia on the cytotoxicity of concomitant KW-2149 and ionizing irradiation in Chinese hamster fibroblasts.
abstract: 7-N-((2-((2-(gamma-L-glutamylamino)ethyl)dithio)ethyl))-mitomycin C (KW-2149) is a newly synthesized water-soluble mitomycin C (MMC) analog. Preclinical testing showed an interesting activity profile and a superior hematological tolerance in murine models. The aim of this study was to investigate the interaction of this compound with ionizing radiation, both under normoxic and hypoxic conditions, in Chinese hamster fibroblasts (V79). V79 cells were irradiated both under normoxic conditions and after a 1 h period of hypoxia. Paired irradiation dose-response curves confirmed the significance of radioresistance under hypoxia with an oxygen enhancement ratio of approximately 3. In contrast to MMC, KW-2149 showed no increased cytotoxic effect on hypoxic V79 cells. The cytotoxic effect of KW-2149 increased with increasing concentration, irrespective of the ambient oxygen pressure. When KW-2149 was combined with irradiation under hypoxic conditions, cytotoxicity was significantly enhanced under these conditions. The difference in survival between normoxic and hypoxic conditions was statistically significant (p < 0.004). These data suggest a radiosensitizing effect of KW-2149, more pronounced under hypoxic conditions. This effect increases with radiation dose. It also corroborates earlier suggestions of a different mode of action of KW-2149 as compared to MMC.
authors.affiliation: Laboratory of Cancer Research and Clinical Oncology, Antwerp University, Edegem, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Egelmeers
authors.forename: L Y
authors.initials: LY
authors.lastname: Dirix
authors.forename: J
authors.initials: J
authors.lastname: Lyczek
authors.forename: E A
authors.initials: EA
authors.lastname: De Bruijn
authors.forename: A T
authors.initials: AT
authors.lastname: Van Oosterom
authors.forename: P
authors.initials: P
authors.lastname: Scalliet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects* / Q000528:radiation effects*; D015687:Cell Hypoxia; D002460:Cell Line / Q000187:drug effects / Q000528:radiation effects; D006224:Cricetinae; D016685:Mitomycin / Q000494:pharmacology; D008937:Mitomycins
chemical_list: D000970:Antineoplastic Agents; D008937:Mitomycins; C057625:KW 2149; D016685:Mitomycin