title: Studies with bifunctional bioreductive drugs. II. Cytotoxicity assayed with A-549 lung carcinoma cells of human origin.
abstract: A lung carcinoma cell line of human origin (A-549) cultured in vitro was used to investigate the cytotoxic effect of a range of bifunctional bioreductive drugs. The drugs tested consisted of nitroimidazoles or nitrofurans with terminal aziridine rings on the side chain and are designated RSU-1069, RSU-1164, RB-7040, RB-88716, and RB-88712. Measurements of the cytotoxicity in air demonstrated that methyl and alkyl addition to the aziridine ring reduced cell killing with progressive substitution of the alkylating moiety. A comparison was made of cytotoxicity in air and hypoxia with cells exposed to drugs for a 4-h period. A direct comparison of the aerobic and hypoxic cytotoxicity of RSU-1069 in human (A-549) and rodent cells (V-79-379A) yielded similar results. The cytotoxicity factors, defined to be the ratio of drug concentrations under aerobic and hypoxic conditions which result in 10% cell survival, were found to be 40, 25, 18, and 8, respectively, for the four agents RSU-1069, RSU-1164, RB-88712, and RB-88716 tested in A-549 cells. It has been suggested that under aerobic conditions the aziridine ring is primarily responsible for aerobic toxicity, whereas under hypoxic conditions, the aziridine moiety combined with a reduced 2-nitro moiety produces a bifunctional agent (I. J. Stratford et al., Br. J. Cancer 53, 339-344, 1986).
authors.affiliation: Center for Radiological Research, Columbia University College of Physicians and Surgeons, New York, New York 10032.
authors.forename: L
authors.initials: L
authors.lastname: Roizin-Towle
authors.forename: J P
authors.initials: JP
authors.lastname: Pirro
authors.forename: E J
authors.initials: EJ
authors.lastname: Hall
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms; D008920:Misonidazole / Q000031:analogs & derivatives / Q000494:pharmacology; D009581:Nitrofurans / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: C049944:1-(2-nitro-1-imidazoly)-3-(2,3-dimethylaziridino)-2-propanol; D000970:Antineoplastic Agents; D001388:Aziridines; D009581:Nitrofurans; C066400:RB 88712; D011838:Radiation-Sensitizing Agents; C049942:RB 7040; C066399:RB 88716; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole