title: Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity.
abstract: OBJECTIVE
  Tirapazamine (TPZ) reportedly enhances the tumor cell killing effect of cisplatin up to fivefold and it is an attractive drug for combination with radiotherapy. We evaluated the toxicity of a fractionated combined treatment.
  
  
  METHODS
  Murine RIF-1 fibrosarcomas growing on the right hind foot of C3-H mice were used. Within 2 weeks, animals were treated with six i.p. injections of TPZ (43.2-172.8 mg/kg total), and/or cisplatin (24 mg/kg total) and ten fractions of 2 Gy to the tumor. All treatments were carried out under anesthesia. Maximum follow-up was 35 days. The local tumor control was determined by calculating the tumor doubling time t (2vo). In addition to standard toxicity assessment, the major inner organs were examined histologically.
  
  
  RESULTS
  The administration of low TPZ doses to the cisplatin/radiotherapy treatment caused only little changes in tumor doubling time (t (2vo)) and led to a lethality rate of 15-30%. Higher TPZ doses caused an increase in t (2vo), but also a further increase in lethality and toxicity in particular to the heart, liver, kidney and stomach. Cisplatin/radiotherapy treatment without TPZ produced no severe toxicity.
  
  
  CONCLUSIONS
  This is a detailed study of both the acute and delayed toxicities of combined TPZ treatment in a mouse model. In our study the addition of TPZ to the cisplatin/radiotherapy treatment caused a significant increase in toxicity with only moderate effect on the tumor.
authors.affiliation: Radiotherapy Practice Weilheim, Weilheim, Germany. adam.markus@gmx.de
authors.forename: Markus
authors.initials: M
authors.lastname: Adam
authors.forename: Christine
authors.initials: C
authors.lastname: Bayer
authors.forename: Julia
authors.initials: J
authors.lastname: Henke
authors.forename: Anca
authors.initials: A
authors.lastname: Grosu
authors.forename: Michael
authors.initials: M
authors.lastname: Molls
authors.forename: Carsten
authors.initials: C
authors.lastname: Nieder
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D006321:Heart / Q000187:drug effects / Q000528:radiation effects; D007668:Kidney / Q000187:drug effects / Q000528:radiation effects; D008099:Liver / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008809:Mice, Inbred C3H; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D013270:Stomach / Q000187:drug effects / Q000528:radiation effects; D015996:Survival Rate; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D015431:Weight Loss
chemical_list: D014227:Triazines; D000077704:Tirapazamine; D002945:Cisplatin