Tirapazamine: from bench to clinical trials.
Tumour hypoxia continues to remain one of the greatest challenges in the treatment of solid tumours. An important avenue to follow with both radiotherapy and chemotherapy is the development of hypoxic cytotoxins such as tirapazamine. The present review covers the history of tirapazamine from preclinical models to clinical trials. The biochemistry as well as the pharmacokinetics of this bioreductive agent are presented. Laboratory data demonstrating the enhanced effect of radiation and cisplatin when combined with tirapazamine are also discussed. There is considerable evidence supporting the potentiation of anti-tumour effect of cisplatin by tirapazamine. Several clinical trials for various tumour sites have been testing the synergistic effect of cisplatin-tirapazamine with and without radiotherapy. These are also reviewed in the present paper. The current literature data on tirapazamine leaves unanswered questions about its action and toxicity. While the current number of phase III trials limits comprehensive conclusions about the administration of this drug, there is a unanimous indication that further clinical studies are warranted.
Marcu
Loredana
L
Royal Adelaide Hospital, Department of Medical Physics, University of Adelaide, School of Chemistry and Physics, Adelaide, Australia. lmarcu@mail.rah.sa.gov.au
Olver
Ian
I
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D002945:Cisplatin