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


Guise CP, Abbattista MR, Tipparaju SR, Lambie NK, Su J, Li D, Wilson WR, Dachs GU, Patterson AV. Diflavin oxidoreductases activate the Bioreductive Prodrug PR-104A under Hypoxia. Mol Pharmacol 81 2012 (1): 1-10.


McKeage MJ, Gu Y, Wilson WR, Hill A, Amies K, Melink TJ, Jameson MB. A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients. BMC Caner. 2011 Oct;11:432.

Benito J, Shi Y, Szymanska B, Carol H, Boehm I, Lu H, Konoplev S, Fang W, Zweidler-McKay PA, Campana D, Borthakur G, Bueso-Ramos C, Shpall E, Thomas DA, Jordan CT, Kantarjian H, Wilson WR, Lock R, Andreeff M, Konopleva M. Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104. PLoS One. 2011 Aug;6(8):e23108. Epub 2011 Aug 11.

Patel K, Choy SS, Hicks KO, Melink TJ, Holford NH, Wilson WR. A combined pharmacokinetic model for the hypoxia-targeted prodrug PR-104A in humans, dogs, rats and mice predicts species differences in clearance and toxicity. Cancer Chemother Pharmacol. 2011 May;67(5):1145-55. Epub 2010 Aug 4.

Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011 Jun;11(6):393-410

Abou-Alfa GK, Chan SL, Lin CC, Chiorean EG, Holcombe RF, Mulcahy MF, Carter WD, Patel K, Wilson WR, Melink TJ, Gutheil JC, Tsao CJ. PR-104 plus sorafenib in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2011 Aug;68(2):539-45. Epub 2011 May 19.

Gu Y, Guise CP, Patel K, Abbattista MR, Lie J, Sun X, Atwell GJ, Boyd M, Patterson AV, Wilson WR. Reductive metabolism of the dinitrobenzamide mustard anticancer prodrug PR-104 in mice. Cancer Chemother Pharmacol. 2011 Mar;67(3):543-55. Epub 2010 May 15.

Gu Y, Tingle MD, Wilson WR. Glucuronidation of Anticancer Prodrug PR-104A: Species Differences, Identification of Human UDP-Glucuronosyltransferases, and Implications for Therapy. J Pharmacol Exp Ther. 2011 Jun;337(3):692-702. Epub 2011 Mar 22.


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


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

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


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


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

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


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


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

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