Faculty of Medical and Health Sciences


Targeting hypoxia: Bioreductive prodrugs

Targeting Hypoxia Bioreductive prodrugs

Bioreductive prodrugs that are selectively activated to cytotoxins under hypoxia in solid tumours have been a focus of the group. We have developed novel benzotriazine dioxides as hypoxia selective cytotoxins in collaboration with Professor Bill Wilson, Dr Frederik Pruijn and Dr Kevin Hicks of the Experimental Therapeutics Group. The culmination of this work has been the discovery of SN30000 which is a second generation analogue of tirapazamine. This compound has undergone preclinical development with Cancer Research UK and we are seeking to conduct first-in-man studies in NZ.

We continue to explore bioreductive prodrugs that release agents within hypoxic areas of tumours. This approach is expected to selectively deliver agents that inhibit the DNA damage response and that synergise with radiation therapy in the context of Head & Neck cancer.

A fundamental aspect of the search for improved bioreductive drugs is defining the radical chemistry of these agents. Studies to explore the radical chemistry of the benzotriazine dioxides and related dioxides are being conducted in collaboration with Associate Professor Bob Anderson.

 

Funding

Financial support from the Health Research Council of NZ, US National Cancer Institute, NIH, Cancer Research UK, Varian Medical Systems, Australian Institute of Nuclear Science and Engineering, Cancer Society NZ, Genesis Oncology Trust, The University of Auckland Biopharma Thematic Research Initiative, and UniServices Ltd is gratefully acknowledged.

 

Related publications

Gu,Y, Jaiswal JK, Wang J, Hicks KO, Hay MP, Wilson WR. Photodegradation of the benzotriazine 1,4-di-N-oxide hypoxia-activated prodrug SN30000 in aqueous solution. J. Pharm. Sci. 103, 3464-3472, 2014. (PMID: 24737463)

Chitneni SK, Bida GT, Yuan H, Palmer GM, Hay MP, Melcher T, Wilson WR, Zalutsky MR, Dewhirst MW. 18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non–small cell lung cancer xenograft model. J Nucl. Med. 54, 1339–1346, 2013. (PMID: 23740105)

Wang J, Foehrenbacher A, Su J, Patel R, Hay MP, Hicks KO, Wilson WR. The 2-nitroimidazole EF5 is a biomarker for oxidoreductases that activate the bioreductive prodrug CEN-209 under hypoxia. Clin. Cancer. Res.18, 1684–1695, 2012. (PMID: 22167409)

Hunter FW, Wang J, Patel R, Hsu H-L, Hickey AJ, Hay MP, Wilson WR. Homologous recombination repair-dependent cytotoxicity of the benzotriazine di-N-oxide CEN-209: comparison with other hypoxia-activated prodrugs. Biochem. Pharmacol. 83, 574–585, 2012. (PMID: 22182429)

Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nature Rev. Cancer 11, 393–410, 2011 (PMID: 21606941).

Hicks KO, Siim BG, Jaiswal JK, Pruijn FB, Fraser AM, Patel R, Hogg A, Liyanage HDS, Dorie MJ, Brown JM, Denny WA, Hay MP, Wilson WR. Pharmacokinetic/ pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic cell killing in tumors. Clin. Cancer Res. 16, 4946–4957, 2010 (PMID: 20732963).

Yadav PJ, Marshall A, Reynisson J, Denny WA, Hay MP, Anderson RF.  Fragmentation of the quinoxaline N-oxide bond to release the •OH radical upon one-electron bioreduction. Chem. Commun. 50, 13729-13731, 2014. (PMID: 25248989)

Anderson RF, Yadav P, Patel D, Reynisson J, Tipparaju SR, Guise CP, Patterson AV. Denny WA, Maroz A, Shinde SS, Hay MP. Characterisation of radicals formed by the anti-tumour compound 3-[3-(4-morpholinyl) propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide, SN30000, a hypoxia-activated prodrug. Org. Biomolec. Chem. 12, 3386-3392, 2014. (PMID: 24737463)

Anderson RF, Shinde SS, Maroz A, Hay MP, Patterson AV, Denny WA. Characterization of radicals formed following enzymatic reduction of 3-substituted analogues of the hypoxia-activated cytotoxin 3-amino-1,2,4 benzotriazine 1,4-dioxide (tirapazamine). J. Am. Chem. Soc. 132, 2591-2599, 2010 (PMID: 20141134).

Shinde SS, Hay MP, Patterson AV, Denny WA, AndersonRF. Spin-trapping of radicals other than the *OH radical upon reduction of the anticancer agent tirapazamine by cytochrome P450 reductase. J. Am. Chem. Soc. 2009, 131, 14220-14221 (PMID: 19772319).