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Hypoxia‐Dependent Retinal Toxicity of NLCQ‐1 (NSC 709257) in BALB/c Mice. Comparison with Tirapazamine
Author(s) -
Papadopoulou Maria V.,
Ji Ming,
Bloomer William D.
Publication year - 2011
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2010.00667.x
Subject(s) - tirapazamine , toxicity , retinal , pharmacology , hypoxia (environmental) , chemistry , retina , biology , biochemistry , cytotoxicity , in vitro , oxygen , organic chemistry , neuroscience
Bioreductive drugs can cause retinal toxicity, mediated by extensive apoptosis in the outer retina of rodents and monkeys. In the present study, we have investigated whether or not the novel and promising hypoxia‐selective cytotoxin 4‐[3‐(2‐nitro‐1‐imidazolyl)‐propylamino]‐7‐chloroquinoline hydrochloride (NLCQ‐1, NSC 709257) can cause hypoxia‐dependent retinal toxicity in BALB/c mice alone or in combination with cyclophosphamide (CPM), one of the anti‐cancer agents that acts synergistically with NLCQ‐1 against mouse tumours and human xenografts. The bioreductive agent tirapazamine (TPZ) was included for comparison purposes. Retinal damage was quantified by morphometric analysis of histological sections following IP treatment of female BALB/c mice. No retinal toxicity was observed with 10 or 22 mg/kg of NLCQ‐1 or 23 mg/kg TPZ alone, whereas statistically significant retinal toxicity was observed with the higher TPZ dose of 52 mg/kg ( p < 0.001). Thus, a normalized photoreceptor layer thickness (NPT) value of 0.50 ± 0.04, 0.48 ± 0.03 and 0.33 ± 0.06 was determined for untreated, NLCQ‐1 and TPZ‐treated mice at the highest dose, respectively. Marginal retinal toxicity was observed with the lower dose of TPZ in combination with CPM.