title: 5-Nitro-4-(N,N-dimethylaminopropylamino)quinoline (5-nitraquine), a new DNA-affinic hypoxic cell radiosensitizer and bioreductive agent: comparison with nitracrine.
abstract: Targeting of electron-affinic radiosensitizers to DNA via noncovalent binding (e.g., intercalation) may offer the potential for increasing sensitizing efficiency. However, it has been suggested that high-affinity DNA binding may compromise sensitization by restricting the mobility of sensitizers along the DNA, and by decreasing rates of extravascular diffusion in tumors. The weak DNA intercalator nitracrine (1-NC) is a more efficient radiosensitizer than related nitroacridines with higher DNA-binding affinities (Roberts et al., Radiat. Res. 123, 153-164, 1990). The present study investigates whether electron-affinic agents of even lower DNA-binding affinity may be superior to nitroacridines. The quinoline analog of 1-NC, 5-nitraquine (5-NO), was shown to have an intrinsic association constant for calf thymus DNA in 20 mM phosphate buffer which was 12-fold lower than that of 1-NC. 5-Nitraquine was not accumulated as efficiently as 1-NC by AA8 cells, but, despite a similar one-electron reduction potential, was 2- to 3-fold more potent than 1-NC as a hypoxia-selective radiosensitizer in vitro when compared on the basis of average intracellular concentration. Thus the radiosensitizing potency of 5-NQ appears not to be compromised by its low DNA-binding affinity. The cytotoxic mechanisms of 5-NQ and 1-NC appear to be similar (hypoxia-selective formation of DNA monoadducts), but 5-NQ is 1200-fold less potent than 1-NC as a cytotoxin. Despite this advantage, 5-NQ was not active in vivo as a radiosensitizer in SCCVII tumors. This lack of activity appears to be due to its relatively high toxicity in vivo (intraperitoneal LD50 of 105 mumol kg-1 in C3H/HeN mice), high one-electron reduction potential (-286 mV), and rapid metabolism to the corresponding amine in mice. The in vitro therapeutic index (hypoxic radiosensitizing potency/aerobic cytotoxic potency) of this weak DNA binder was lower than that of the non-DNA targeted radiosensitizer misonidazole, suggesting that DNA targeting enhances cytotoxicity more than radiosensitization. Development of useful DNA-targeted radiosensitizers may require the exploitation of DNA binding modes different from those of the nitroacridines and nitroquinolines.
authors.affiliation: Department of Pathology, University of Auckland School of Medicine, New Zealand.
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
authors.forename: B G
authors.initials: BG
authors.lastname: Siim
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
authors.forename: P L
authors.initials: PL
authors.lastname: van Zijl
authors.forename: M L
authors.initials: ML
authors.lastname: Taylor
authors.forename: D M
authors.initials: DM
authors.lastname: Chambers
authors.forename: P B
authors.initials: PB
authors.lastname: Roberts
mesh_terms: D000634:Aminoquinolines / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000532:radiotherapy; D009564:Nitracrine / Q000378:metabolism / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D009564:Nitracrine; C077851:5-nitraquine; D004247:DNA