title: The hypoxia-selective cytotoxin NLCQ-1 (NSC 709257) controls metastatic disease when used as an adjuvant to radiotherapy.
abstract: BACKGROUND
  Metastases cause most cancer-related deaths. We investigated the use of hypoxia-selective cytotoxins as adjuvants to radiotherapy in the control of metastatic tumour growth.
  
  
  METHODS
  The NLCQ-1, RB6145 and tirapazamine were assessed against the spontaneously metastasising KHT model. Subcutaneous KHT tumours (250 mm(3)) were irradiated with 25 Gy (single fraction) to control primary growth. Equitoxic drug treatments (NLCQ-1 (10 mg kg(-1)) once daily; RB6145 (75 mg kg(-1)) and tirapazamine (13 mg kg(-1)) twice daily) were administered 3-6 days post-radiotherapy when hypoxic cells were evident in lung micrometastases. Mice were culled when 50% of controls exhibited detrimental signs of lung metastases.
  
  
  RESULTS
  In total, 95% of control mice presented with lung disease. This was significantly reduced by NLCQ-1 (33%; P=0.0002) and RB6145 (60%; P=0.02). Semi-quantitative grading of lung disease revealed a significant improvement with all treatments, with NLCQ-1 proving most efficacious (median grades: control, 4; NLCQ, 0 (P<0.0001); RB6145, 1 (P<0.001), tirapazamine, 3 (P=0.007)). Positron emission tomography (PET) was evaluated as a non-invasive means of assessing metastatic development. Primary and metastatic KHT tumours showed robust uptake of [(18)F]fluorodeoxyglucose ([(18)F]FDG). Metastatic burden discernable by [(18)F]FDG PET correlated well with macroscopic and histological lung analysis.
  
  
  CONCLUSIONS
  The hypoxia-selective cytotoxin NLCQ-1 controls metastatic disease and may be a successful adjuvant to radiotherapy in the clinical setting.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Lunt
authors.forename: C
authors.initials: C
authors.lastname: Cawthorne
authors.forename: M
authors.initials: M
authors.lastname: Ali
authors.forename: B A
authors.initials: BA
authors.lastname: Telfer
authors.forename: M
authors.initials: M
authors.lastname: Babur
authors.forename: A
authors.initials: A
authors.lastname: Smigova
authors.forename: P J
authors.initials: PJ
authors.lastname: Julyan
authors.forename: P M
authors.initials: PM
authors.lastname: Price
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: W D
authors.initials: WD
authors.lastname: Bloomer
authors.forename: M V
authors.initials: MV
authors.lastname: Papadopoulou
authors.forename: K J
authors.initials: KJ
authors.lastname: Williams
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D007093:Imidazoles / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D051379:Mice; D008809:Mice, Inbred C3H; D009362:Neoplasm Metastasis; D009593:Nitroimidazoles / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage*; D012509:Sarcoma / Q000188:drug therapy* / Q000556:secondary*; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage
chemical_list: C434187:4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline hydrochloride; D007093:Imidazoles; D009593:Nitroimidazoles; D011804:Quinolines; D014227:Triazines; C067834:RB 6145; D000077704:Tirapazamine