title: Tirapazamine administered as a neoadjuvant to radiotherapy reduces metastatic dissemination.
abstract: OBJECTIVE
  The level of hypoxia in primary tumors has been linked both clinically and experimentally to the incidence of metastases. This study was designed to address the effect of selectively targeting hypoxic cells in primary tumors on subsequent presentation of metastasis.
  
  
  METHODS
  The murine KHT model was used as a reproducible temporal and spatial onset of metastases is revealed following treatment of primary ( approximately 400 mm(3)) s.c. tumors with a 25 Gy radiation dose. The bioreductive drugs tirapazamine and RB6145 were administered in multiple doses before radiotherapy.
  
  
  RESULTS
  Fractionated treatment with both tirapazamine and RB6145 significantly reduced the hypoxic fraction of the primary tumor, as assessed by pimonidazole binding, and had no effect on the overall growth rate of the primary tumor. Excision assays showed an increased level of cell kill in tirapazamine-treated versus RB6145-treated tumors consistent with tirapazamine targeting hypoxic cells at a broader range of oxygen tensions than RB6145. Tirapazamine treatment significantly reduced the presentation of metastases following radiotherapy (P = 0.003 versus saline controls) whereas RB6145 had no effect. Local control rates increased from 20% to 32% and 50% when radiation was combined with RB6145 and tirapazamine, respectively.
  
  
  CONCLUSIONS
  These data provide direct evidence that selective targeting of hypoxic cells in primary tumors is a viable approach in the control of metastatic disease. The enhanced efficacy of tirapazamine versus RB6145 suggests that the radioresistant cells at intermediate oxygen tensions, conducive to targeting with tirapazamine but not with the more stringent bioreductive RB6145, predominate in terms of linking primary tumor hypoxia and metastases.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Sarah Jane
authors.initials: SJ
authors.lastname: Lunt
authors.forename: Brian A
authors.initials: BA
authors.lastname: Telfer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Fitzmaurice
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: Kaye J
authors.initials: KJ
authors.lastname: Williams
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D000860:Hypoxia; D051379:Mice; D008809:Mice, Inbred C3H; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D000077704:Tirapazamine; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D014227:Triazines; C067834:RB 6145; D000077704:Tirapazamine