News & Events
Publications
The following are key publications on physiologically-targeted prodrugs and tumor hypoxia by Proacta's scientists and advisors:
2010
Denny WA. Hypoxia-activated prodrugs in cancer therapy: progress to the clinic. Future Oncol 2010 Mar;6(3):419-28
Finger EC, Giaccia AJ. Hypoxia, inflammation, and the tumor microenvironment in metastatic disease. Cancer Metastasis Rev 2010 Jun;29(2):285-93
Gu Y, Atwell GJ, Wilson WR. Metabolism and excretion of the novel bioreductive prodrug PR-104 in mice, rats, dogs, and humans. Drug Metab Dispos 2010 Mar;38(3):498-508
Gu Y, Guise CP, Patel K, Abbattista MR, Lie J, Sun X, et al. Reductive metabolism of the dinitrobenzamide mustard anticancer prodrug PR-104 in mice. Cancer Chemother Pharmacol 2010 May 15;
Guise CP, Abbattista MR, Singleton RS, Holford SD, Connolly J, Dachs GU, et al. The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3. Cancer Res 2010 Feb 15;70(4):1573-84
Jameson MB, Rischin D, Pegram M, Gutheil J, Patterson AV, Denny WA, et al. A phase I trial of PR-104, a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3, in patients with solid tumors. Cancer Chemother Pharmacol 2010 Mar;65(4):791-801
2009
Cairns RA, Bennewith KL, Graves EE, Giaccia AJ, Chang DT, Denko NC. Pharmacologically increased tumor hypoxia can be measured by 18F-Fluoroazomycin arabinoside positron emission tomography and enhances tumor response to hypoxic cytotoxin PR-104. Clin Cancer Res 2009 Dec 1;15(23):7170-4
Gu Y, Patterson AV, Atwell GJ, Chernikova SB, Brown JM, Thompson LH, et al. Roles of DNA repair and reductase activity in the cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A. Mol Cancer Ther 2009 Jun;8(6):1714-23
Gu Y, Wilson WR. Rapid and sensitive ultra-high-pressure liquid chromatography-tandem mass spectrometry analysis of the novel anticancer agent PR-104 and its major metabolites in human plasma: Application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2009 Oct 1;877(27):3181-6
Milbank JB, Stevenson RJ, Ware DC, Chang JY, Tercel M, Ahn GO, et al. Synthesis and evaluation of stable bidentate transition metal complexes of 1-(chloromethyl)-5-hydroxy-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihy dro-1H-pyrrolo[3,2-f]quinoline (seco-6-azaCBI-TMI) as hypoxia selective cytotoxins. J Med Chem 2009 Nov 12;52(21):6822-34
Singleton RS, Guise CP, Ferry DM, Pullen SM, Dorie MJ, Brown JM, et al. DNA cross-links in human tumor cells exposed to the prodrug PR-104A: relationships to hypoxia, bioreductive metabolism, and cytotoxicity. Cancer Res 2009 May 1;69(9):3884-91
Tercel M, Atwell GJ, Yang S, Stevenson RJ, Botting KJ, Boyd M, et al. Hypoxia-activated prodrugs: substituent effects on the properties of nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (nitroCBI) prodrugs of DNA minor groove alkylating agents. J Med Chem 2009 Nov 26;52(22):7258-72
Wilson WR, Stribbling SM, Pruijn FB, Syddall SP, Patterson AV, Liyanage HD, et al. Nitro-chloromethylbenzindolines: hypoxia-activated prodrugs of potent adenine N3 DNA minor groove alkylators. Mol Cancer Ther 2009 Oct;8(10):2903-13
2008
Hay MP, Hicks KO, Pchalek K, Lee HH, Blaser A, Pruijn FB, et al. Tricyclic [1,2,4]triazine 1,4-dioxides as hypoxia selective cytotoxins. J Med Chem 2008 Nov 13;51(21):6853-65
Helsby NA, Goldthorpe MA, Tang MH, Atwell GJ, Smith EM, Wilson WR, et al. Influence of mustard group structure on pathways of in vitro metabolism of anticancer N-(2-hydroxyethyl)-3,5-dinitrobenzamide 2-mustard prodrugs. Drug Metab Dispos 2008 Feb;36(2):353-60
Liu SC, Ahn GO, Kioi M, Dorie MJ, Patterson AV, Brown JM. Optimized clostridium-directed enzyme prodrug therapy improves the antitumor activity of the novel DNA cross-linking agent PR-104. Cancer Res 2008 Oct 1;68(19):7995-8003
Pruijn FB, Patel K, Hay MP, Wilson WR, Hicks KO. Prediction of Tumour Tissue Diffusion Coefficients of Hypoxia-Activated Prodrugs from Physicochemical Parameters. Australian Journal of Chemistry 2008 Sep 5;61(9):687-93
Wilson WR, Hicks KO, Pruijn FB, Patterson AV. Targeting Tumor Hypoxia with Prodrugs: Challenges and Opportunities. Am Assoc Cancer Res Educ Book 2008;1:293-310
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]anilino]ethyl methanesulfonate (PR-104). Journal of Labelled Compounds and Radiopharmaceuticals 2007 Jan 22;50:7-14
Brown JM. Tumor hypoxia in cancer therapy. Methods Enzymol 2007;435:297-321
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 2007 Sep 15;74(6):810-20
Hay MP, Hicks KO, Pruijn FB, Pchalek K, Siim BG, Wilson WR, et al. 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 2007 Dec 13;50(25):6392-404
Hay MP, Pchalek K, Pruijn FB, Hicks KO, Siim BG, Anderson RF, et al. 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 2007 Dec 27;50(26):6654-64
Hicks KO, Myint H, Patterson AV, Pruijn FB, Siim BG, Patel K, et al. Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: comparison of the dinitrobenzamide mustard PR-104A and tirapazamine. Int J Radiat Oncol Biol Phys 2007 Oct 1;69(2):560-71
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 2007 Sep 1;856(1-2):302-11
Patterson AV, Ferry DM, Edmunds SJ, Gu Y, Singleton RS, Patel K, et al. Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent PR-104. Clin Cancer Res 2007 Jul 1;13(13):3922-32
Wilson WR, Hicks KO, Pullen SM, Ferry DM, Helsby NA, Patterson AV. Bystander effects of bioreductive drugs: potential for exploiting pathological tumor hypoxia with dinitrobenzamide mustards. Radiat Res 2007 Jun;167(6):625-36
2006
Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006 Apr 27;440(7088):1222-6
Hicks KO, Pruijn FB, Secomb TW, Hay MP, Hsu R, Brown JM, et al. Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs. J Natl Cancer Inst 2006 Aug 16;98(16):1118-28
Tatum JL, Kelloff GJ, Gillies RJ, Arbeit JM, Brown JM, Chao KS, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol 2006 Oct;82(10):699-757
2005
Anderson RF, Shinde SS, Hay MP, Gamage SA, Denny WA. Radical properties governing the hypoxia-selective cytotoxicity of antitumor 3-amino-1,2,4-benzotriazine 1,4-dioxides. Org Biomol Chem 2005 Jun 7;3(11):2167-74
2004
Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004 Jun;4(6):437-47
Denny WA. Tumor-activated prodrugs--a new approach to cancer therapy. Cancer Invest 2004;22(4):604-19
Denny WA. Prospects for hypoxia-activated anticancer drugs. Curr Med Chem Anticancer Agents 2004 Sep;4(5):395-9
2002
Brown JM. Tumor microenvironment and the response to anticancer therapy. Cancer Biol Ther 2002 Sep;1(5):453-8
Back to top
