title: Hypoxia-dependent retinal toxicity of NLCQ-1 (NSC 709257) in BALB/c mice. Comparison with tirapazamine.
abstract: 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.
authors.affiliation: Department of Radiation Medicine, NorthShore University HealthSystem, Evanston, IL 60201, USA. mpapadopoulou@northshore.org
authors.forename: Maria V
authors.initials: MV
authors.lastname: Papadopoulou
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.forename: William D
authors.initials: WD
authors.lastname: Bloomer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D003603:Cytotoxins / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D012160:Retina / Q000187:drug effects* / Q000503:physiopathology; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: C434187:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride; D000970:Antineoplastic Agents; D003603:Cytotoxins; D007093:Imidazoles; D011804:Quinolines; D014227:Triazines; D000077704:Tirapazamine; D003520:Cyclophosphamide