MedKoo product information:

 Tirapazamine

Tirapazamine is a benzotriazine di-N-oxide with potential antineoplastic activity. Tirapazamine is selectively activated by multiple reductases to form free radicals in hypoxic cells, thereby inducing single-and double-strand breaks in DNA, base damage, and cell death. This agent also sensitizes hypoxic cells to ionizing radiation and inhibits the repair of radiation-induced DNA strand breaks via inhibition of topoisomerase II. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Sanofi-Synthelabo (Originator), SRI (Originator), National Cancer Institute (Not Determined)

Phase I study of Tirapazamine: Eleven patients were enrolled. The median age was 52 years (range, 31-65 years). Ten patients had squamous cell carcinoma and 1 patient had adenocarcinoma; 5 patients had stage 1B2 disease, 1 had stage IIA, 3 had stage IIB-3, 1 had stage IIIB, and 1 had stage IVA. The first 2 patients on dose level 1 experienced a dose-limiting toxicity (DLT): 1 experienced grade 3 alanine amino transferase elevation and grade 4 pulmonary embolism, and 1 experienced grade 3 ototoxicity. Doses were decreased to dose level -1 with a 30-mg/m dose of cisplatin and a 260-mg/m dose of tirapazamine. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a: a 35-mg/m dose of cisplatin and a 260-mg/m doses of tirapazamine with 2 DLTs--grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. Three of 10 evaluable patients have experienced locoregional failure. The combination of weekly tirapazamine and cisplatin with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being tirapazamine 260 mg/m and cisplatin 30 mg/m. Further study of this weekly schedule is not warranted. (source: Int J Gynecol Cancer. 2010 Jul;20(5):827-33.)

1: Reddy SB, Williamson SK. Tirapazamine: a novel agent targeting hypoxic tumor cells. Expert Opin Investig Drugs. 2009 Jan;18(1):77-87. doi: 10.1517/13543780802567250 . Review. PubMed PMID: 19053884.

2: Marcu L, Olver I. Tirapazamine: from bench to clinical trials. Curr Clin Pharmacol. 2006 Jan;1(1):71-9. Review. PubMed PMID: 18666379.

3: Gandara DR, Lara PN Jr, Goldberg Z, Le QT, Mack PC, Lau DH, Gumerlock PH. Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia. Semin Oncol. 2002 Feb;29(1 Suppl 4):102-9. Review. PubMed PMID: 11894020.

4: Denny WA, Wilson WR. Tirapazamine: a bioreductive anticancer drug that exploits tumour hypoxia. Expert Opin Investig Drugs. 2000 Dec;9(12):2889-901. Review. PubMed PMID: 11093359.

5: Patterson AV, Saunders MP, Chinje EC, Patterson LH, Stratford IJ. Enzymology of tirapazamine metabolism: a review. Anticancer Drug Des. 1998 Sep;13(6):541-73. Review. PubMed PMID: 9755718.

6: Brown JM, Wang LH. Tirapazamine: laboratory data relevant to clinical activity. Anticancer Drug Des. 1998 Sep;13(6):529-39. Review. PubMed PMID: 9755717.

7: Gatzemeier U, Rodriguez G, Treat J, Miller V, von Roemeling R, Viallet J, Rey A. Tirapazamine-cisplatin: the synergy. Br J Cancer. 1998 Jun;77 Suppl 4:15-7. Review. PubMed PMID: 9647615; PubMed Central PMCID: PMC2149886.

8: Brown JM. Exploiting tumour hypoxia and overcoming mutant p53 with tirapazamine. Br J Cancer. 1998 Jun;77 Suppl 4:12-4. Review. PubMed PMID: 9647614; PubMed Central PMCID: PMC2149884.

9: Brown JM. SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours. Br J Cancer. 1993 Jun;67(6):1163-70. Review. PubMed PMID: 8512801; PubMed Central PMCID: PMC1968495.