title: Advantage of combining NLCQ-1 (NSC 709257) with radiation in treatment of human head and neck xenografts.
abstract: NLCQ-1 (NSC 709257), a hypoxia-selective cytotoxin that targets DNA through weak intercalation, was investigated for efficacy in combination with single or fractionated radiotherapy of human head and neck xenografts. A staged tumor experiment was performed in tumor-bearing female athymic nude mice that were locally irradiated with or without NLCQ-1. Tumor hypoxia was assessed by immunohistochemistry for pimonidazole adducts in tumors of varying weight. Fractionated radiation, depending on the dose, was administered either once daily for 4 days or once daily for 4 days followed by a 7-day rest and repeat. NLCQ-1 was administered i.p. at 15 mg/kg alone or 45 min before each radiation dose. Hypoxia (1-52%) was detected in all tumors and was positively correlated with tumor size. NLCQ-1 alone resulted in about 10 days of tumor growth delay, measured at sixfold the tumor's original size, without causing toxicity. All combination treatments with NLCQ-1 were more effective than treatments with radiation alone. Radiation at 1 Gy given once daily for 4 days on days 20 and 30 caused 3.5 days of tumor growth delay, whereas in combination with NLCQ-1 it caused 14.5 days of growth delay. Radiation at 5 Gy given in two doses 10 days apart resulted in 3.5 days of tumor growth delay, whereas more than 20 additional days of delay were observed in combination with NLCQ-1. Radiation given as a single dose of 10 Gy resulted in about 7 days of tumor growth delay, whereas in combination with NLCQ-1 about 30 additional days of delay were seen. These results suggest a significant advantage in combining radiation with NLCQ-1 in treatment of human head and neck tumors, which are known to have hypoxic areas.
authors.affiliation: Department of Radiation Medicine, Evanston Northwestern Healthcare, Evanston, Illinois 60201, USA. m-papadopoulou@northwestern.edu
authors.forename: Maria V
authors.initials: MV
authors.lastname: Papadopoulou
authors.forename: William D
authors.initials: WD
authors.lastname: Bloomer
authors.forename: Alice P
authors.initials: AP
authors.lastname: Taylor
authors.forename: Marisol
authors.initials: M
authors.lastname: Hernandez
authors.forename: Rosalyn D
authors.initials: RD
authors.lastname: Blumenthal
authors.forename: Melinda G
authors.initials: MG
authors.lastname: Hollingshead
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006258:Head and Neck Neoplasms / Q000178:diet therapy* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D011804:Quinolines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: C434187:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride; D007093:Imidazoles; D011804:Quinolines