title: NLA-1: a 2-nitroimidazole radiosensitizer targeted to DNA by intercalation.
abstract: Targeting of electron affinic radiosensitizers to DNA via reversible non-covalent intercalative binding has potential for increasing sensitizer concentrations locally at the DNA target while decreasing accessibility to reductases responsible for bioactivation and cytotoxicity. We have prepared an DNA-targeted acridine-linked 2-nitroimidazole (NLA-1) as an example of such a compound. NLA-1 binds reversibly to DNA with an affinity similar to 9-aminoacridine, and is approximately 1000 times more potent than MISO as a cytotoxin, despite a similar reduction potential. It shows less enhancement of cytotoxicity under hypoxia (5- to 6-fold) than does MISO (approximately 11-fold), but is a potent hypoxia-selective radiosensitizer in AA8 cells with a concentration for an enhancement ratio of 1.6 (C1.6) of 9 microM. The mean intracellular concentration at the C1.6 is 400 microM, on which basis its potency is about twice that of MISO. The in vitro therapeutic index (aerobic cytotoxic potency/hypoxic C1.6) of NLA-1 is approximately 6-fold lower than that for MISO. NLA-1 lacks radiosensitizing activity against SCCVII or EMT6 tumors in vivo at the maximum tolerated dose (MTD) of 100 mumol.kg-1.
authors.affiliation: Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
authors.forename: P B
authors.initials: PB
authors.lastname: Roberts
authors.forename: R F
authors.initials: RF
authors.lastname: Anderson
authors.forename: J M
authors.initials: JM
authors.lastname: Brown
authors.forename: D
authors.initials: D
authors.lastname: Phil
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
mesh_terms: D000609:Aminoacridines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002460:Cell Line; D003131:Combined Modality Therapy; D004247:DNA / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D007364:Intercalating Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy*; D009593:Nitroimidazoles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000609:Aminoacridines; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C072689:NLA 1; D004247:DNA