Auckland Cancer Society Research Centre

SN 30000 and related tirapazamine analogues as hypoxia-selective anticancer drugs

Project leaders

Research overview

A major research project for our group has been the development of novel benzotriazine dioxides as 2nd generation analogues of the hypoxia selective prodrug, Tirapazamine (TPZ). Funded by the National Cancer Institute, USA, this project was achieved in collaboration with the Medicinal Chemistry Group and Professor Martin Brown, Department of Radiation Oncology, Stanford University.

Medicinal Chemistry Group

Professor Martin Brown

These bioreductive drugs are selectively activated to cytotoxins in the areas of low oxygen found in solid tumours. We showed that, although TPZ has many desirable properties, its poor penetration limited its ability to reach its target hypoxic cells, which are generally the cells furthest away from blood vessels. To develop a TPZ analogue with improved transport properties we used diffusion measurements in multicellular layers to transport page to validate a predictive model of drug transport and activity in tumours and showed that this model could be used to guide TPZ analogue development (See Hicks et al 2006, below). This allowed prediction of which analogues designed by the Medicinal Chemistry Group would penetrate into tumours better than TPZ and hence should proceed to in vivo testing.

SN 30000 is the lead analogue from this program which has markedly improved penetration and is superior to TPZ in tumour xenografts. In addition it has improved solubility to TPZ which will improve its ease of use in patients. SN 30000 is likely proceed to Phase I clinical trials shortly.

Staff involved on this project

Selected publications on TPZ analogues

Pruijn FB, Patel K, Hay MP, Wilson WR, Hicks KO (2008) Prediction of tumour tissue diffusion coefficients of hypoxia-activated prodrugs from physicochemical parameters. Aust J Chem 61: 687-693. 

Hay MP, Hicks KO, Pchalek K, Lee HH, Blaser A, Pruijn FB, Anderson RF, Shinde SS, Wilson WR, Denny WA (2008) Tricyclic [1,2,4]triazine 1,4-dioxides as hypoxia selective cytotoxins. J Med Chem 51: 6853-6865. 

Evans JW, Chernikova SB, Kachnic LA, Banath JP, Sordet O, Delahoussaye YM, et al (2008). Homologous recombination is the principal pathway for the repair of DNA damage induced by tirapazamine in mammalian cells. Cancer Res; 68(1):257-65. 

Hay MP, Hicks KO, Pruijn FB, Pchalek K, Siim BG, Wilson WR, Denny WA (2007) Pharmacokinetic/Pharmacodynamic model-guided identification of hypoxia-selective 1,2,4-benzotriazine 1,4-dioxides with antitumor activity: the role of extravascular transport. J Med Chem 50: 6392-6404. 

Hicks KO, Myint H, Patterson AV, Pruijn FB, Siim BG, Patel K, Wilson WR (2007) Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: comparison of the dinitrobenzamide mustard PR-104A and tirapazamine. Int J Radiat Oncol Biol Phys 69: 560-571. 

Hay MP, Pchalek K, Pruijn FB, Hicks KO, Siim BG, Anderson RF, Shinde SS, Phillips V, Denny WA, Wilson WR (2007) Hypoxia-selective 3-alkyl 1,2,4-benzotriazine 1,4-dioxides: the influence of hydrogen bond donors on extravascular transport and antitumor activity. J Med Chem 50: 6654-6664.

Hicks, KO, Pruijn, FB, Secomb, TW, Hay, MP, Hsu, R, Brown, JM, Denny, WA, Dewhirst, MW, Wilson, W. R. (2006) Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs. J. Natl Cancer Inst. 98(16), 1118-1128. 

Pruijn, FB, Sturman, J, Liyanage, S, Hicks, KO, Hay, MP, Wilson, WR (2005) Extravascular transport of drugs in tumor tissue: Effect of lipophilicity on diffusion of tirapazamine analogues in multicellular layer cultures. J. Med. Chem. 48, 1079–1087.

Denny WA (2005). Hypoxia-activated anticancer drugs. Expert Opinion on Therapeutic Patents 15(6):635-46.

Hicks, KO, Siim BG, Pruijn FB, Wilson, WR (2004) Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implications for extravascular transport and activity in tumors. Radiat Res. 161, 656-66.

Brown JM, Wilson WR (2004). Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4(6):437-47.

Hay MP, Pruijn FB, Gamage SA, Liyanage HD, Kovacs MS, Patterson AV, et al (2004). DNA-targeted 1,2,4-benzotriazine 1,4-dioxides: potent analogues of the hypoxia-selective cytotoxin tirapazamine. J Med Chem;47(2):475-88.

Hicks, KO, Pruijn, FB, Sturman, JR, Denny, WA, Wilson, WR (2003) Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in HT29 multicellular layer cultures. Cancer Res., 63, 5970-7.

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

Hicks, KO, Fleming, Y, Siim, BG, Koch, CJ, Wilson, WR (1998) Extravascular diffusion of tirapazamine: effect of metabolic consumption assessed using the multicellular layer model. Int J Radiat Oncol Biol Phys, 42, 641-9.