title: THNLA-1 as radio/chemosensitiser of EMT-6 tumours in mice.
abstract: THNLA-1 contains a 2-nitroimidazole tethered to 9-amino-1,2,3,4-tetrahydroacridine. Compared with its parent acridinic analogue, NLA-1, THNLA-1 is a weak DNA-affinic bioreductive compound with a greater mobility along the DNA backbone, decreased aerobic toxicity, greater hypoxic selectivity and a superior in vitro therapeutic index. Also, THNLA-1 behaves as a radio/chemosensitiser in vitro. In this report we have expanded our radio/chemosensitisation studies in vivo, using the EMT-6 mouse mammary tumour model in balb/c mice and the in vivo-in vitro assay. THNLA-1 was given i.p. ( < or = 0.5 ml in saline) at various time intervals before a single dose of 20 Gy whole-body irradiation. Tumours were excised immediately or 24 h after irradiation. Radiosensitisation studies with SR-2508 (i.v.) have been performed in a similar way for comparison purposes. THNLA-1 demonstrated the same radiosensitising effect as SR-2508 but with 19-fold less dose (mmol kg-1). The optimum effect was observed when THNLA-1 was given 1 h before irradiation and the tumours excised 24 h after irradiation. Chemosensitisation studies in the same tumour model and using cis DDP showed that the cytotoxic effect of cis-DDP (5 or 8 mg kg-1, i.p.) was significantly enhanced with 30 or 45 mg kg-1 THNLA-1 given approximately 3 h before cis-DDP. A similar potentiating effect was observed when NLA-1 (27 or 30 mg kg-1) was used, but toxicity was also observed at the higher dose. Limited toxicity studies showed that THNLA-1 is well tolerated up to at least 70 mg kg-1 as a single dose, for more than 40 days.
authors.affiliation: Evanston Hospital Corp., Department of Radiation Medicine, IL 60201, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Papadopoulou
authors.forename: M
authors.initials: M
authors.lastname: Ji
authors.forename: W D
authors.initials: WD
authors.lastname: Bloomer
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D017341:Etanidazole / Q000494:pharmacology; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013619:Tacrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D011838:Radiation-Sensitizing Agents; C092966:9-(3-(2-nitro-1-imidazolyl)propylamino)-1,2,3,4-tetrahydroacridine; D017341:Etanidazole; D013619:Tacrine; D002945:Cisplatin