Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity

J Cancer Res Clin Oncol. 2008 Feb;134(2):137-46. doi: 10.1007/s00432-007-0260-7. Epub 2007 Jul 11.


Purpose: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cisplatin / administration & dosage
  • Combined Modality Therapy
  • Heart / drug effects
  • Heart / radiation effects
  • Kidney / drug effects
  • Kidney / radiation effects
  • Liver / drug effects
  • Liver / radiation effects
  • Mice
  • Mice, Inbred C3H
  • Sarcoma, Experimental / drug therapy
  • Sarcoma, Experimental / radiotherapy
  • Sarcoma, Experimental / therapy*
  • Stomach / drug effects
  • Stomach / radiation effects
  • Survival Rate
  • Tirapazamine
  • Triazines / administration & dosage
  • Tumor Cells, Cultured
  • Weight Loss


  • Triazines
  • Tirapazamine
  • Cisplatin