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.