In vitro hypoxic cytotoxicity and hypoxic radiosensitization. Efficacy of the novel 2-nitroimidazole N,N,N-tris[2-(2-nitro-1H-imidazol-1-yl)ethyl]amine.
OBJECTIVE
Tumor hypoxia is a major problem in radiation therapy of solid tumors because of the radiosensitizing effect of oxygen. Nitroimidazole-containing compounds are oxygen mimetics accumulating in hypoxic tumor areas. However, the broad use of 2-nitroimidazoles as a hypoxic radiosensitizer is limited by their partially low efficacy and/or high neurotoxicity.


METHODS
Here, we characterized the in vitro hypoxic cytotoxicity and hypoxic radiosensitizing efficacy of N,N,N-tris [2-(2-nitro-1H-imidazol-1-yl)ethyl]amine (PRC) in a hypoxia-sensitive lymphoma and a hypoxia-resistant glioblastoma cell line by colony formation assay and flow cytometry.


RESULTS
PRC exerted high hypoxic cytotoxic and radiosensitizing action on both cell lines at almost absent toxicity under normoxic conditions. In particular, under hypoxia, but not normoxia, PRC targeted the mitochondria resulting in oxidative stress, G(2)/M cell cycle arrest, and triggering of the intrinsic apoptosis pathway.


CONCLUSIONS
Our in vitro findings suggest that PRC might be a promising new 2-nitroimidazole for improving radiation therapy of hypoxic tumors in vivo.
Department of Radiation Oncology, Eberhard-Karls-University of Tübingen, Tübingen, Germany.
M
M
Langenbacher
R J
RJ
Abdel-Jalil
W
W
Voelter
M
M
Weinmann
S M
SM
Huber
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D019169:Jurkat Cells; D008928:Mitochondria / Q000187:drug effects; D009593:Nitroimidazoles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D005021:Ethylamines; C579807:N,N,N-tris(2-(2-nitro-1H-imidazol-1-yl)ethyl)amine; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species