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Journal Publications

The following are recent publications on physiologically-targeted prodrugs and tumor hypoxia by Proacta's scientists and advisors:

Review

Brown J.M. Tumor hypoxia in cancer therapy. Methods Enzymol. 435: 297-321, 2007.

Brown J.M. and Wilson W.R. Exploiting tumor hypoxia in cancer treatment. Nature Rev. Cancer 4: 437-447, 2004.

Denny, W.A. Prospects for hypoxia-activated anticancer drugs. Curr. Med. Chem.-Anticancer Agents, 4: 395-399, 2004.

Denny, W.A. Tumor-activated prodrugs - a new approach to cancer chemotherapy. Cancer Inv., 22: 604-619, 2004.

2007

Wilson WR, Hicks KO, Pullen SM, Ferry DM, Helsby MA, Patterson AV. Bystander effects of bioreductive drugs: potential for exploiting tumour hypoxia with dinitrobenzamide mustards. Rad Res 167(6): 625-636, 2007.

Hicks KO, Myint H, Patterson AV, Pruijn FB, Siim BG, Patel K, Wilson WR. Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: comparison of the dinitrobenzamide mustard PR-104A and tirapazamine. Int J Radiat Oncol Biol Phys. 1;69(2): 560-71, 2007.

Guise CP, Wang AT, Theil A, Bridewell DJ, Wilson WR, Patterson AV. Identification of human reductases that activate the dinitrobenzamide mustard prodrug PR-104A: a role for NADPH:cytochrome P450 oxidoreductase under hypoxia. Biochem Pharmacol. 74(6):810-20, 2007.

Patel K, Lewiston D, Gu Y, Hicks KO, Wilson WR. Analysis of the hypoxia-activated dinitrobenzamide mustard phosphate pre-prodrug PR-104 and its alcohol metabolite PR-104A in plasma and tissues by liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 856(1-2):302-11, 2007.

Patterson AV, Ferry DM, Edmunds SJ, Gu Y, Singleton RS, Patel K, Pullen SM, Hicks KO, Syddall SP, Atwell GJ, Yang S, Denny WA, Wilson WR. Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent PR-104. Clin Cancer Res. 13(13):3922-32, 2007.

Atwell GJ, Denny WA. Synthesis of 3H and 2H4 labelled versions of the hypoxia-activated pre-prodrug 2-[(2-bromoethyl)-2,4-dinitro-6-[[[2-(phosphonooxy)ethyl]amino]carbonyl]aniline]ethyl methanesulfonate (PR-104). Journal of Labelled Compounds and Radiopharmaceuticals. 50: 7-12 2007.

Hay MP, Pchalek K, Pruijn FB, Hicks KO, Siim BG, Anderson RF, Shinde SS, Phillips V, Denny WA, Wilson WR. 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(26):6654-64, 2007.

Hay MP, Hicks KO, Pruijn FB, Pchalek K, Siim BG, Wilson WR, Denny WA. 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, 2007.

Singleton DC, Li D, Bai SY, Syddall SP, Smaill JB, Post LE, Denny WA, Wilson WR, Patterson AV. The nitroreductase prodrug SN 28343 enhances the potency of the systemically administered armed oncolytic adenovirus ONYX-411NTR. Cancer Gene Therapy, 14, 953-967, 2007.

Yang S, Atwell GJ, Denny WA. A new synthesis of asymmetric dinitrobenzamide mustards. Tetrahedron, 63, 5470-5476, 2007.

Atwell GJ, Yang S, Pruijn FB, Pullen SM, Hogg A, Patterson AV, Wilson WR, Denny WA. Synthesis and structure-activity relationships for 2,4-dinitrobenzamide-5-mustards as prodrugs for the E. coli nitroreductase (NTR) in gene therapy. J. Med. Chem., 50, 1197-1212, 2007.

2006

Anderson, R.F., Shinde, S., Hay, M.P., Denny, W.A. Redox equilibria of benzotriazine N-oxide compounds that potentiate the cytotoxicity of the anticancer benzotriazine 1,4-dioxide, tirapazamine. J. Amer. Chem. Soc., 128: 245-249, 2006.

Erler J.T., Bennewith, K.L., Nicolau, M., Dornhofer, N., Kong, C., Le, Q.T., Chi, J.T., Jeffrey, S.S., Giaccia, A.J. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 440:1222-6, 2006.

Hicks KO, Pruijn FB, Secomb TW, Hay MP, Hsu R, Brown JM, Denny WA, Dewhirst MW, Wilson WR. 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):1118-28, 2006.

2005

Anderson, R.F., Shinde, S.S., Hay, M.P., Gamage, S.A., Denny, W.A. Radical factors governing the hypoxia selectivity of antitumour 1,2,4-benzotriazine 1,4-dioxides. Org. Biomol. Chem., 3: 2167-2174, 2005.

Hay M.P., Wilson W.R., Denny W.A. Nitroarylmethylcarbamate prodrugs of doxorubicin for use with nitroreductase gene-directed enzyme prodrug therapy. Bioorganic & Medicinal Chemistry 13: 4043-4055, 2005

Nelson, D.W., Cao, H., Zhu, Y., Sunar-Reeder, B., Choi, C.Y.H., Faix, J.D, Brown, J.M., Koong, A.C., Giaccia, A.J., and Le, Q-T. (2005) A Noninvasive Approach for Assessing Tumor Hypoxia in Xenografts: Developing a Urinary Marker for Hypoxia. Cancer Res. 65(14): 6151-6158.

Pruijn, F.B., Sturman, J., Liyanage, S., Hicks, K.O., Hay, M. P. and Wilson, W.R. Extravascular transport of drugs in tumor tissue: Effect of lipophilicity on diffusion of tirapazamine analogs in multicellular layer cultures. J. Med. Chem. 48: 1079-1087, 2005.

Tang, M.H.Y., Helsby, N.A., Wilson, W.R. and Tingle, M.D. Aerobic 2- and 4-nitroreduction of CB 1954 by human liver. Toxicology 216: 129-139, 2005.

2004

Ahn, G.-O., Ware, D.C., Denny, W.A., Wilson, W.R. Optimization of the auxiliary ligand shell of cobalt(III)(8-hydroxyquinoline) complexes as model hypoxia-selective radiation-activated prodrugs. Radiation Res., 162: 315-325, 2004.

Craig, P.R., Brothers, P.J., Clark, G.R., Wilson, W.R., Denny, W.A., Ware, D.C. Anionic carbonato and oxalato cobalt(III) nitrogen mustard complexes. J. Chem. Soc., Dalton Trans., 611-618, 2004.

Hay, M.P., Pruijn, F.B., Gamage, S.A., Liyanage, H.D.S., Kovacs, M.S., Patterson, A.V., Wilson, W.R., Brown, J.M., Denny, W.A. DNA-targeted 1,2,4-Benzotriazine 1,4-Dioxides as Hypoxia-Selective Analogues of Tirapazamine, J. Med. Chem., 47: 475-488, 2004.

Hicks, K.O., Siim, B.G., Pruijn, F.B. and Wilson W.R. Oxygen dependence of the metabolic activation and cytotoxicity of tirapazamine: implication for extravascular transport and activity in tumors. Radiat. Res., 6: 656-666, 2004

Helsby, N.A., Atwell, G.J., Yang, S., Palmer, B.D., Anderson, R.F., Pullen, S.M., Ferry, D.M., Hogg, A., Wilson W.R. and Denny, W.A. Aziridinyldinitrobenzamides: synthesis and structure-activity relationships for activation by E. coli nitroreductase. J. Med. Chem., 47: 3295-3307, 2004

Helsby, N.A., Ferry, D.M., Patterson, A.V., Pullen, S.M. and Wilson , W.R. 2-Amino metabolites are key mediators of CB 1954 and SN 23862 in nitroreductase GDEPT. Br. J. Cancer, 90: 1084-1093, 2004

Shinde, S., Anderson, R.F., Hay, M.P., Gamage, S.A. and Denny, W.A. Oxidation of 2-deoxyribose by benzotriazinyl radicals of antitumor 3-aminobenzotriazine 1,4-dioxides. J. Amer. Chem. Soc. 126, 7865-7874, 2004.

Siim, B.G., Pruijn, F.B. Sturman, J., Hogg, A., Brown, J.M. and Wilson , W.R. Selective potentiation of the hypoxic cytotoxicity of tirapazamine by its 1- N -oxide metabolite SR 4317. Cancer Res., 64: 736-742, 2004.

2003

Hay, M.P., Gamage,S.A., Kovacs, M.S., Pruijn,F.B., Anderson,R.F., Patterson,A.V., Wilson,W.R., Brown,J.M. and Denny,W.A. Structure-activity relationships of 1,2,4-benzotriazine 1,4-dioxides as hypoxia-selective analogs of tirapazamine. J. Med. Chem, 46: 169-182, 2003.

Hay, M.P., Atwell, G.J., Wilson, W.R., Pullen, S.M., and Denny, W.A. Structure-activity relationships for 4-nitrobenzyl carbamates of 5-aminobenz[e]indoline minor groove alkylating agents as prodrugs for GDEPT in conjunction with E. coli nitroreductase. J. Med. Chem., 46: 2456-2466, 2003.

Helsby, N.A., Wheeler, J.S., Pruijn, F.B., Palmer, B.D., Yang, S., Denny, W.A. and Wilson, W.R. Effect of nitroreduction on the alkylating reactivity and cytotoxicity of the 2,4-dinitrobenzamide aziridine CB 1954 and the corresponding nitrogen mustard SN 23862. Distinct mechanisms of bioreductive activation. Chem. Res. Toxicol. 16: 469-478, 2003.

Hicks, K.O., Pruijn, F.B., Sturman, J., Denny, W.A. and Wilson, W.R. Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in HT29 multicellular layers. Cancer Res. 63: 5970-5977, 2003.

Siim, B.G., Lee, A.E., Shalal-Zwain, S., Pruijn, F.B., McKeage, M., and Wilson , W.R. Marked potentiation of the antitumor activity of chemotherapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Cancer Chemother. Pharmacol., 51: 43-52, 2003

Wilson, W.R., Pullen, S.M., Hogg, A., Hobbs, S.M., Pruijn, F.B. and Hicks, K.O. In vitro and in vivo models for evaluation of GDEPT: quantifying bystander killing in cell cultures and tumors. In: Suicide Gene Therapy: Methods and Reviews. (Ed CJ Springer). Humana Press, Totowa , N.J. pp403-432, 2003.