title: Selective toxicity of a quinoxaline 1,4-di-N-oxide derivative in human tumour cell lines.
abstract: The presence of hypoxic cells in human solid tumours is one of the causes of tumour resistance to conventional therapy, and is also associated with processes that promote the tumour progression. Different chemical agents have been designed in order to take advantage of the particular metabolic characteristics of hypoxic regions. These drugs, called bioreductive agents, are activated inside the hypoxic cells to give active species that, in the presence of oxygen, are oxidised back to the non-toxic parent compound. Several quinoxaline 1,4-di-N-oxides have been described as potential bioreductive agents, and among them, 7-cloro-3-[[(N,N-dimethylamino)propy]amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxide hydrocloride (Q-85 HCl) appeared to be the most promising one. In the present work, the selective cytotoxicity of Q-85 HCl was studied in several human tumour cell lines of different origin (Caco2, MCF-7, HT-29 and Tk-10). Cell viability was calculated after 2 h treatment under hypoxic and well-oxygenated conditions. The potency (the concentration that gives 1% of cell survival) in hypoxia and hypoxia cytotoxicity ratio (HCR = potency in oxygenated conditions/potency in hypoxia) were calculated after a 14-day clonogenic assay. Q-85 HCl was more toxic in hypoxia than in well-oxygenated cells in all the tumour cell lines. The best profile of potency in hypoxia (0.4 micromol/L) and selectivity (HCR=155) was found in CaCo-2 cells. Altogether, these results suggest an in vitro biological profile for Q-85 HCl that makes it an interesting candidate for the development as a bioreductive agent.
authors.affiliation: Centro de Investigación en Farmacobiologia Aplicada, University of Navarra, Pamplona, Spain.
authors.forename: Azquetaa
authors.initials: A
authors.lastname: Amaia
authors.forename: Gisela
authors.initials: G
authors.lastname: Pachón
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
authors.forename: Edmond E
authors.initials: EE
authors.lastname: Creppy
authors.forename: Antonio
authors.initials: A
authors.lastname: Monge
authors.forename: Adela
authors.initials: A
authors.lastname: López de Cerain
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011810:Quinoxalines / Q000633:toxicity*; D014410:Tumor Stem Cell Assay
chemical_list: C108265:7-chloro-3-(((N,N-dimethylamino)propyl)amino)-2-quinoxalinecarbonitrile-1,4-di-N-oxide; D000970:Antineoplastic Agents; D011810:Quinoxalines