Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs Cytotoxic Reviews Godefridus J. Peters and Eric Raymond

Cancer Chemotherapy and Pharmacology

Volumn 77, Issue 3, 2016, Pages 441-457

  Phillips, Roger M ^a  

^a UNIVERSITY OF HUDDERSFIELD   (United Kingdom)

Author keywords

AQ4N; Bioreductive drugs; EO9; Hypoxia; Hypoxia activated prodrugs; PR 104; TH 302; TH 4000; Tirapazamine

Indexed keywords

BANOXANTRONE; EVOFOSFAMIDE; HYPOXIA ACTIVATED PRODRUG; OXIDOREDUCTASE; PR 104; PRODRUG; TH 4000; TIRAPAZAMINE; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; OXYGEN;

ANTINEOPLASTIC ACTIVITY; CANCER CHEMOTHERAPY; DRUG MECHANISM; DRUG SCREENING; DRUG TARGETING; HUMAN; HYPOXIA; HYPOXIC CELL; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; TUMOR CELL; ANIMAL; CELL HYPOXIA; DRUG DELIVERY SYSTEM; DRUG DESIGN; METABOLISM; NEOPLASMS; PATHOLOGY; PHYSIOLOGY; TUMOR MICROENVIRONMENT;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL HYPOXIA; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; NEOPLASMS; OXIDOREDUCTASES; OXYGEN; PRODRUGS; TUMOR MICROENVIRONMENT;

EID: 84959507403     PISSN: 03445704     EISSN: 14320843     Source Type: Journal    
DOI: 10.1007/s00280-015-2920-7     Document Type: Review

References (128)

1. Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93:266-276
2. Lee CT, Boss MK, Dewhirst MW (2014) Imaging tumor hypoxia to advance radiation oncology. Antioxid Redox Signal 21:313-337
3. Koch CJ, Jenkins WT, Jenkins KW, Yang XY, Shuman AL, Pickup S, Riehl CR, Paudyal R, Poptani H, Evans SM (2013) Mechanisms of blood flow and hypoxia production in rat 9L-epigastric tumors. Tumor Microenviron Ther 1:1-13
4. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88-91
5. Luoto KR, Kumareswaran R, Bristow RG (2013) Tumor hypoxia as a driving force in genetic instability. Genome Integr 4:5
6. Chang Q, Jurisica I, Do T, Hedley DW (2011) Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res 71:3110-3120
7. Harris AL (2002) Hypoxia-a key regulatory factor in tumour growth. Nat Rev Cancer 2:38-47
8. Gluck AA, Aebersold DM, Zimmer Y, Medova M (2015) Interplay between receptor tyrosine kinases and hypoxia signaling in cancer. Int J Biochem Cell Biol 62:101-114
9. Barsoum IB, Smallwood CA, Siemens DR, Graham CH (2014) A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 74:665-674
10. Viry E, Paggetti J, Baginska J, Mgrditchian T, Berchem G, Moussay E, Janji B (2014) Autophagy: an adaptive metabolic response to stress shaping the antitumor immunity. Biochem Pharmacol 92:31-42
11. Sun RC, Denko NC (2014) Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab 19:285-292
12. Kucharzewska P, Christianson HC, Belting M (2015) Global profiling of metabolic adaptation to hypoxic stress in human glioblastoma cells. PLoS ONE 10:e0116740
13. Intlekofer AM, Dematteo RG, Venneti S, Finley LW, Lu C, Judkins AR, Rustenburg AS, Grinaway PB, Chodera JD, Cross JR, Thompson CB (2015) Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab 22:304-311
14. Oldham WM, Clish CB, Yang Y, Loscalzo J (2015) Hypoxia-mediated increases in l-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab 22:291-303
15. Ye J, Wu D, Wu P, Chen Z, Huang J (2014) The cancer stem cell niche: cross talk between cancer stem cells and their microenvironment. Tumour Biol 35:3945-3951
16. Balamurugan K (2016) HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer 138:1058-1066
17. Pires IM, Blokland NJ, Broos AW, Poujade FA, Senra JM, Eccles SA, Span PN, Harvey AJ, Hammond EM (2014) HIF-1alpha-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion. Cancer Biol Ther 15:1350-1357
18. Gray LH, Conger AO, Ebert M, Hornsey S, Scott OCA (1953) The concentration of oxygen dissolved in tissue at the time of irradiation as a factor in radiotherapy. Br J Radiol 26:638-648
19. Grepin R, Pages G (2010) Molecular mechanisms of resistance to tumour anti-angiogenic strategies. J Oncol 2010:835680
20. Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441-1454
21. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393-410
22. Ahmadi M, Ahmadihosseini Z, Allison SJ, Begum S, Rockley K, Sadiq M, Chintamaneni S, Lokwani R, Hughes N, Phillips RM (2014) Hypoxia modulates the activity of a series of clinically approved tyrosine kinase inhibitors. Br J Pharmacol 171:224-236
23. Hammond EM, Asselin MC, Forster D, O'Connor JP, Senra JM, Williams KJ (2014) The meaning, measurement and modification of hypoxia in the laboratory and the clinic. Clin Oncol (R Coll Radiol) 26:277-288
24. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225-239
25. Lin AJ, Cosby LA, Shansky CW, Sartorelli AC (1972) Potential bioreductive alkylating agents. 1. Benzoquinone derivatives. J Med Chem 15:1247-1252
26. Teicher BA, Sartorelli AC (1980) Nitrobenzyl halides and carbamates as prototype bioreductive alkylating agents. J Med Chem 23:955-960
27. Guise CP, Mowday AM, Ashoorzadeh A, Yuan R, Lin WH, Wu DH, Smaill JB, Patterson AV, Ding K (2014) Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia. Chin J Cancer 33:80-86
28. Denny WA, Wilson WR, Hay MP (1996) Recent developments in the design of bioreductive drugs. Br J Cancer Suppl 27:S32-S38
29. Workman P (1994) Enzyme-directed bioreductive drug development revisited: a commentary on recent progress and future prospects with emphasis on quinone anticancer agents and quinone metabolizing enzymes, particularly DT-diaphorase. Oncol Res 6:461-475
30. Duan JX, Jiao H, Kaizerman J, Stanton T, Evans JW, Lan L, Lorente G, Banica M, Jung D, Wang J, Ma H, Li X, Yang Z, Hoffman RM, Ammons WS, Hart CP, Matteucci M (2008) Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. J Med Chem 51:2412-2420
31. Meng F, Evans JW, Bhupathi D, Banica M, Lan L, Lorente G, Duan JX, Cai X, Mowday AM, Guise CP, Maroz A, Anderson RF, Patterson AV, Stachelek GC, Glazer PM, Matteucci MD, Hart CP (2012) Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. Mol Cancer Ther 11:740-751
32. Saggar JK, Tannock IF (2014) Activity of the hypoxia-activated pro-drug TH-302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy. Int J Cancer 134:2726-2734
33. Wojtkowiak JW, Cornnell HC, Matsumoto S, Saito K, Takakusagi Y, Dutta P, Kim M, Zhang X, Leos R, Bailey KM, Martinez G, Lloyd MC, Weber C, Mitchell JB, Lynch RM, Baker AF, Gatenby RA, Rejniak KA, Hart C, Krishna MC, Gillies RJ (2015) Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302. Cancer Metab 3:2
34. Hu J, Van Valckenborgh E, Xu D, Menu E, De Raeve H, De Bryune E, Xu S, Van Camp B, Handisides D, Hart CP, Vanderkerken K (2013) Synergistic induction of apoptosis in multiple myeloma cells by bortezomib and hypoxia-activated prodrug TH-302, in vivo and in vitro. Mol Cancer Ther 12:1763-1773
35. Liapis V, Labrinidis A, Zinonos I, Hay S, Ponomarev V, Panagopoulos V, DeNichilo M, Ingman W, Atkins GJ, Findlay DM, Zannettino AC, Evdokiou A (2015) Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma. Cancer Lett 357:160-169
36. Meng F, Bhupathi D, Sun JD, Liu Q, Ahluwalia D, Wang Y, Matteucci MD, Hart CP (2015) Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition. BMC Cancer 15:422
37. Peeters SG, Zegers CM, Biemans R, Lieuwes NG, van Stiphout RG, Yaromina A, Sun JD, Hart CP, Windhorst AD, van Elmpt W, Dubois LJ, Lambin P (2015) TH-302 in combination with radiotherapy enhances the therapeutic outcome and is associated with pretreatment [18F]HX4 hypoxia PET imaging. Clin Cancer Res 21:2984-2992
38. Saggar JK, Tannock IF (2015) Chemotherapy rescues hypoxic tumor cells and induces their reoxygenation and repopulation-an effect that is inhibited by the hypoxia-activated prodrug TH-302. Clin Cancer Res 21:2107-2114
39. Sun JD, Liu Q, Ahluwalia D, Li W, Meng F, Wang Y, Bhupathi D, Ruprell AS, Hart CP (2015) Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer. Cancer Biol Ther 16:438-449
40. Yoon C, Lee HJ, Park DJ, Lee YJ, Tap WD, Eisinger-Mathason TS, Hart CP, Choy E, Simon MC, Yoon SS (2015) Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas. Br J Cancer 113:46-56
41. Portwood S, Lal D, Hsu YC, Vargas R, Johnson MK, Wetzler M, Hart CP, Wang ES (2013) Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models. Clin Cancer Res 19:6506-6519
42. Ganjoo KN, Cranmer LD, Butrynski JE, Rushing D, Adkins D, Okuno SH, Lorente G, Kroll S, Langmuir VK, Chawla SP (2011) A phase I study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. Oncology 80:50-56
43. Weiss GJ, Infante JR, Chiorean EG, Borad MJ, Bendell JC, Molina JR, Tibes R, Ramanathan RK, Lewandowski K, Jones SF, Lacouture ME, Langmuir VK, Lee H, Kroll S, Burris HA 3rd (2011) Phase 1 study of the safety, tolerability, and pharmacokinetics of TH-302, a hypoxia-activated prodrug, in patients with advanced solid malignancies. Clin Cancer Res 17:2997-3004
44. Weiss GJ, Lewandowski K, Oneall J, Kroll S (2011) Resolution of Cullen's sign in patient with metastatic melanoma responding to hypoxia-activated prodrug TH-302. Dermatol Rep 3:e56
45. Chawla SP, Cranmer LD, Van Tine BA, Reed DR, Okuno SH, Butrynski JE, Adkins DR, Hendifar AE, Kroll S, Ganjoo KN (2014) Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. J Clin Oncol 32:3299-3306
46. Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, Schelman WR, Stephenson J Jr, Chiorean EG, Rosen PJ, Ulrich B, Dragovich T, Del Prete SA, Rarick M, Eng C, Kroll S, Ryan DP (2015) Randomized phase II trial of gemcitabine plus TH-302 versus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 33:1475-1481
47. Oostveen EA, Speckamp WN (1987) Mitomycin analogs I. Indolequinones as (potential)bis alkylating agents. Tetrahedron 43:255-262
48. Phillips RM, Hendriks HR, Peters GJ, Pharmacology E, Molecular Mechanism G (2013) EO9 (Apaziquone): from the clinic to the laboratory and back again. Br J Pharmacol 168:11-18
49. Plumb JA, Workman P (1994) Unusually marked hypoxic sensitization to indoloquinone EO9 and mitomycin C in a human colon-tumour cell line that lacks DT-diaphorase activity. Int J Cancer 56:134-139
50. Robertson N, Haigh A, Adams GE, Stratford IJ (1994) Factors affecting sensitivity to EO9 in rodent and human tumour cells in vitro: DT-diaphorase activity and hypoxia. Eur J Cancer 30A:1013-1019
51. Traver RD, Siegel D, Beall HD, Phillips RM, Gibson NW, Franklin WA, Ross D (1997) Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase). Br J Cancer 75:69-75
52. Hendriks HR, Pizao PE, Berger DP, Kooistra KL, Bibby MC, Boven E, Dreef-van der Meulen HC, Henrar RE, Fiebig HH, Double JA et al (1993) EO9: a novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models. Eur J Cancer 29A:897-906
53. McLeod HL, Graham MA, Aamdal S, Setanoians A, Groot Y, Lund B (1996) Phase I pharmacokinetics and limited sampling strategies for the bioreductive alkylating drug EO9. EORTC Early Clinical Trials Group. Eur J Cancer 32A:1518-1522
54. Schellens JH, Planting AS, van Acker BA, Loos WJ, de Boer-Dennert M, van der Burg ME, Koier I, Krediet RT, Stoter G, Verweij J (1994) Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug E09. J Natl Cancer Inst 86:906-912
55. Dirix LY, Tonnesen F, Cassidy J, Epelbaum R, ten Bokkel Huinink WW, Pavlidis N, Sorio R, Gamucci T, Wolff I, Te Velde A, Lan J, Verweij J (1996) EO9 phase II study in advanced breast, gastric, pancreatic and colorectal carcinoma by the EORTC Early Clinical Studies Group. Eur J Cancer 32A:2019-2022
56. Pavlidis N, Hanauske AR, Gamucci T, Smyth J, Lehnert M, te Velde A, Lan J, Verweij J (1996) A randomized phase II study with two schedules of the novel indoloquinone EO9 in non-small-cell lung cancer: a study of the EORTC Early Clinical Studies Group (ECSG). Ann Oncol 7:529-531
57. Connors TA (1996) Bioreductive agents, hypoxic cells and therapy. Eur J Cancer 32A:1833-1834
58. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6:583-592
59. Phillips RM, Loadman PM, Cronin BP (1998) Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumours. Br J Cancer 77:2112-2119
60. Choudry GA, Stewart PA, Double JA, Krul MR, Naylor B, Flannigan GM, Shah TK, Brown JE, Phillips RM (2001) A novel strategy for NQO1 (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2) mediated therapy of bladder cancer based on the pharmacological properties of EO9. Br J Cancer 85:1137-1146
61. Puri R, Palit V, Loadman PM, Flannigan M, Shah T, Choudry GA, Basu S, Double JA, Lenaz G, Chawla S, Beer M, Van Kalken C, de Boer R, Beijnen JH, Twelves CJ, Phillips RM (2006) Phase I/II pilot study of intravesical apaziquone (EO9) for superficial bladder cancer. J Urol 176:1344-1348
62. van der Heijden AG, Moonen PM, Cornel EB, Vergunst H, de Reijke TM, van Boven E, Barten EJ, Puri R, van Kalken CK, Witjes JA (2006) Phase II marker lesion study with intravesical instillation of apaziquone for superficial bladder cancer: toxicity and marker response. J Urol 176:1349-1353 (discussion 1353)
63. Hendricksen K, van der Heijden AG, Cornel EB, Vergunst H, de Reijke TM, van Boven E, Smits GA, Puri R, Gruijs S, Witjes JA (2009) Two-year follow-up of the phase II marker lesion study of intravesical apaziquone for patients with non-muscle invasive bladder cancer. World J Urol 27:337-342
64. Jain A, Phillips RM, Scally AJ, Lenaz G, Beer M, Puri R (2009) Response of multiple recurrent TaT1 bladder cancer to intravesical apaziquone (EO9): comparative analysis of tumor recurrence rates. Urology 73:1083-1086
65. Hendricksen K, Gleason D, Young JM, Saltzstein D, Gershman A, Lerner S, Witjes JA (2008) Safety and side effects of immediate instillation of apaziquone following transurethral resection in patients with nonmuscle invasive bladder cancer. J Urol 180:116-120
66. Nishida CR, Ortiz de Montellano PR (2008) Reductive heme-dependent activation of the n-oxide prodrug AQ4N by nitric oxide synthase. J Med Chem 51:5118-5120
67. Raleigh SM, Wanogho E, Burke MD, McKeown SR, Patterson LH (1998) Involvement of human cytochromes P450 (CYP) in the reductive metabolism of AQ4 N, a hypoxia activated anthraquinone di-N-oxide prodrug. Int J Radiat Oncol Biol Phys 42:763-767
68. Patterson LH, McKeown SR (2000) AQ4 N: a new approach to hypoxia-activated cancer chemotherapy. Br J Cancer 83:1589-1593
69. Mehibel M, Singh S, Chinje EC, Cowen RL, Stratford IJ (2009) Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4 N). Mol Cancer Ther 8:1261-1269
70. McKeown SR, Hejmadi MV, McIntyre IA, McAleer JJ, Patterson LH (1995) AQ4 N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo. Br J Cancer 72:76-81
71. Patterson LH, McKeown SR, Ruparelia K, Double JA, Bibby MC, Cole S, Stratford IJ (2000) Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4 N, a bioreductively activated anti-tumour agent. Br J Cancer 82:1984-1990
72. Friery OP, Gallagher R, Murray MM, Hughes CM, Galligan ES, McIntyre IA, Patterson LH, Hirst DG, McKeown SR (2000) Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine. Br J Cancer 82:1469-1473
73. Tredan O, Garbens AB, Lalani AS, Tannock IF (2009) The hypoxia-activated ProDrug AQ4N penetrates deeply in tumor tissues and complements the limited distribution of mitoxantrone. Cancer Res 69:940-947
74. Ming L, Byrne NM, Camac SN, Mitchell CA, Ward C, Waugh DJ, McKeown SR, Worthington J (2013) Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumours: informed scheduling of the bioreductive drug AQ4N improves treatment response. Int J Cancer 132:1323-1332
75. Gieling RG, Fitzmaurice RJ, Telfer BA, Babur M, Williams KJ (2015) Dissemination via the lymphatic or angiogenic route impacts the pathology, microenvironment and hypoxia-related drug response of lung metastases. Clin Exp Metastasis 32:567-577
76. Williams KJ, Albertella MR, Fitzpatrick B, Loadman PM, Shnyder SD, Chinje EC, Telfer BA, Dunk CR, Harris PA, Stratford IJ (2009) In vivo activation of the hypoxia-targeted cytotoxin AQ4N in human tumor xenografts. Mol Cancer Ther 8:3266-3275
77. O'Rourke M, Ward C, Worthington J, McKenna J, Valentine A, Robson T, Hirst DG, McKeown SR (2008) Evaluation of the antiangiogenic potential of AQ4 N. Clin Cancer Res 14:1502-1509
78. Albertella MR, Loadman PM, Jones PH, Phillips RM, Rampling R, Burnet N, Alcock C, Anthoney A, Vjaters E, Dunk CR, Harris PA, Wong A, Lalani AS, Twelves CJ (2008) Hypoxia-selective targeting by the bioreductive prodrug AQ4N in patients with solid tumors: results of a phase I study. Clin Cancer Res 14:1096-1104
79. Papadopoulos KP, Goel S, Beeram M, Wong A, Desai K, Haigentz M, Milian ML, Mani S, Tolcher A, Lalani AS, Sarantopoulos J (2008) A phase 1 open-label, accelerated dose-escalation study of the hypoxia-activated prodrug AQ4N in patients with advanced malignancies. Clin Cancer Res 14:7110-7115
80. Steward WP, Middleton M, Benghiat A, Loadman PM, Hayward C, Waller S, Ford S, Halbert G, Patterson LH, Talbot D (2007) The use of pharmacokinetic and pharmacodynamic end points to determine the dose of AQ4N, a novel hypoxic cell cytotoxin, given with fractionated radiotherapy in a phase I study. Ann Oncol 18:1098-1103
81. 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 (2007) Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent PR-104. Clin Cancer Res 13:3922-3932
82. Guise CP, Wang AT, Theil A, Bridewell DJ, Wilson WR, Patterson AV (2007) Identification of human reductases that activate the dinitrobenzamide mustard prodrug PR-104A: a role for NADPH:cytochrome P450 oxidoreductase under hypoxia. Biochem Pharmacol 74:810-820
83. Hunter FW, Jaiswal JK, Hurley DG, Liyanage HD, McManaway SP, Gu Y, Richter S, Wang J, Tercel M, Print CG, Wilson WR, Pruijn FB (2014) The flavoprotein FOXRED2 reductively activates nitro-chloromethylbenzindolines and other hypoxia-targeting prodrugs. Biochem Pharmacol 89:224-235
84. Guise CP, Abbattista MR, Singleton RS, Holford SD, Connolly J, Dachs GU, Fox SB, Pollock R, Harvey J, Guilford P, Donate F, Wilson WR, Patterson AV (2010) The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3. Cancer Res 70:1573-1584
85. Guise CP, Abbattista MR, Tipparaju SR, Lambie NK, Su J, Li D, Wilson WR, Dachs GU, Patterson AV (2012) Diflavin oxidoreductases activate the bioreductive prodrug PR-104A under hypoxia. Mol Pharmacol 81:31-40
86. Gu Y, Patterson AV, Atwell GJ, Chernikova SB, Brown JM, Thompson LH, Wilson WR (2009) Roles of DNA repair and reductase activity in the cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A. Mol Cancer Ther 8:1714-1723
87. Hunter FW, Hsu HL, Su J, Pullen SM, Wilson WR, Wang J (2014) Dual targeting of hypoxia and homologous recombination repair dysfunction in triple-negative breast cancer. Mol Cancer Ther 13:2501-2514
88. Moradi Manesh D, El-Hoss J, Evans K, Richmond J, Toscan CE, Bracken LS, Hedrick A, Sutton R, Marshall GM, Wilson WR, Kurmasheva RT, Billups C, Houghton PJ, Smith MA, Carol H, Lock RB (2015) AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. Blood 126:1193-1202
89. Houghton PJ, Lock R, Carol H, Morton CL, Phelps D, Gorlick R, Kolb EA, Keir ST, Reynolds CP, Kang MH, Maris JM, Wozniak AW, Gu Y, Wilson WR, Smith MA (2011) Initial testing of the hypoxia-activated prodrug PR-104 by the pediatric preclinical testing program. Pediatr Blood Cancer 57:443-453
90. 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 (2011) Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104. PLoS ONE 6:e23108
91. Foehrenbacher A, Secomb TW, Wilson WR, Hicks KO (2013) Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling. Front Oncol 3:314
92. Foehrenbacher A, Patel K, Abbattista MR, Guise CP, Secomb TW, Wilson WR, Hicks KO (2013) The role of bystander effects in the antitumor activity of the hypoxia-activated prodrug PR-104. Front Oncol 3:263
93. Abbattista MR, Jamieson SM, Gu Y, Nickel JE, Pullen SM, Patterson AV, Wilson WR, Guise CP (2015) Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma. Cancer Biol Ther 16:610-622
94. Cairns RA, Bennewith KL, Graves EE, Giaccia AJ, Chang DT, Denko NC (2009) 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 15:7170-7174
95. Jameson MB, Rischin D, Pegram M, Gutheil J, Patterson AV, Denny WA, Wilson WR (2010) 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 65:791-801
96. McKeage MJ, Gu Y, Wilson WR, Hill A, Amies K, Melink TJ, Jameson MB (2011) A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients. BMC Cancer 11:432
97. McKeage MJ, Jameson MB, Ramanathan RK, Rajendran J, Gu Y, Wilson WR, Melink TJ, Tchekmedyian NS (2012) PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours. BMC Cancer 12:496
98. 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 (2011) PR-104 plus sorafenib in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 68:539-545
99. Gu Y, Tingle MD, Wilson WR (2011) Glucuronidation of anticancer prodrug PR-104A: species differences, identification of human UDP-glucuronosyltransferases, and implications for therapy. J Pharmacol Exp Ther 337:692-702
100. Konopleva M, Thall PF, Yi CA, Borthakur G, Coveler A, Bueso-Ramos C, Benito J, Konoplev S, Gu Y, Ravandi F, Jabbour E, Faderl S, Thomas D, Cortes J, Kadia T, Kornblau S, Daver N, Pemmaraju N, Nguyen HQ, Feliu J, Lu H, Wei C, Wilson WR, Melink TJ, Gutheil JC, Andreeff M, Estey EH, Kantarjian H (2015) Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia. Haematologica 100:927-934
101. Shinde SS, Hay MP, Patterson AV, Denny WA, Anderson RF (2009) Spin trapping of radicals other than the OH radical upon reduction of the anticancer agent tirapazamine by cytochrome P450 reductase. J Am Chem Soc 131:14220-14221
102. Patterson AV, Robertson N, Houlbrook S, Stephens MA, Adams GE, Harris AL, Stratford IJ, Carmichael J (1994) The role of DT-diaphorase in determining the sensitivity of human tumor cells to tirapazamine (SR 4233). Int J Radiat Oncol Biol Phys 29:369-372
103. Marcu L, Olver I (2006) Tirapazamine: from bench to clinical trials. Curr Clin Pharmacol 1:71-79
104. Le QT, Moon J, Redman M, Williamson SK, Lara PN Jr, Goldberg Z, Gaspar LE, Crowley JJ, Moore DF Jr, Gandara DR (2009) Phase II study of tirapazamine, cisplatin, and etoposide and concurrent thoracic radiotherapy for limited-stage small-cell lung cancer: SWOG 0222. J Clin Oncol 27:3014-3019
105. Miller VA, Ng KK, Grant SC, Kindler H, Pizzo B, Heelan RT, von Roemeling R, Kris MG (1997) Phase II study of the combination of the novel bioreductive agent, tirapazamine, with cisplatin in patients with advanced non-small-cell lung cancer. Ann Oncol 8:1269-1271
106. Rischin D, Peters L, Fisher R, Macann A, Denham J, Poulsen M, Jackson M, Kenny L, Penniment M, Corry J, Lamb D, McClure B (2005) Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J Clin Oncol 23:79-87
107. Treat J, Johnson E, Langer C, Belani C, Haynes B, Greenberg R, Rodriquez R, Drobins P, Miller W Jr, Meehan L, McKeon A, Devin J, von Roemeling R, Viallet J (1998) Tirapazamine with cisplatin in patients with advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 16:3524-3527
108. Williamson SK, Crowley JJ, Lara PN, Jr., McCoy J, Lau DH, Tucker RW, Mills GM, Gandara DR, Southwest Oncology Group Trial S (2005) Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol 23:9097-9104
109. Rischin D, Peters LJ, O'Sullivan B, Giralt J, Fisher R, Yuen K, Trotti A, Bernier J, Bourhis J, Ringash J, Henke M, Kenny L (2010) Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol 28:2989-2995
110. DiSilvestro PA, Ali S, Craighead PS, Lucci JA, Lee YC, Cohn DE, Spirtos NM, Tewari KS, Muller C, Gajewski WH, Steinhoff MM, Monk BJ (2014) Phase III randomized trial of weekly cisplatin and irradiation versus cisplatin and tirapazamine and irradiation in stages IB2, IIA, IIB, IIIB, and IVA cervical carcinoma limited to the pelvis: a Gynecologic Oncology Group study. J Clin Oncol 32:458-464
111. Brown JM (2012) Imaging tumor sensitivity to a bioreductive prodrug: two for the price of one! Clin Cancer Res 18:1487-1489
112. Peters LJ, O'Sullivan B, Giralt J, Fitzgerald TJ, Trotti A, Bernier J, Bourhis J, Yuen K, Fisher R, Rischin D (2010) Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02. J Clin Oncol 28:2996-3001
113. Le QT, Fisher R, Oliner KS, Young RJ, Cao H, Kong C, Graves E, Hicks RJ, McArthur GA, Peters L, O'Sullivan B, Giaccia A, Rischin D (2012) Prognostic and predictive significance of plasma HGF and IL-8 in a phase III trial of chemoradiation with or without tirapazamine in locoregionally advanced head and neck cancer. Clin Cancer Res 18:1798-1807
114. Lim AM, Rischin D, Fisher R, Cao H, Kwok K, Truong D, McArthur GA, Young RJ, Giaccia A, Peters L, Le QT (2012) Prognostic significance of plasma osteopontin in patients with locoregionally advanced head and neck squamous cell carcinoma treated on TROG 02.02 phase III trial. Clin Cancer Res 18:301-307
115. Mack PC, Redman MW, Chansky K, Williamson SK, Farneth NC, Lara PN Jr, Franklin WA, Le QT, Crowley JJ, Gandara DR, Swog (2008) Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG Study S0003. J Clin Oncol 26:4771-4776
116. Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, Peters LJ, Trans-Tasman Radiation Oncology Group S (2006) Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02. J Clin Oncol 24:2098-2104
117. Trinkaus ME, Hicks RJ, Young RJ, Peters LJ, Solomon B, Bressel M, Corry J, Fisher R, Binns D, McArthur GA, Rischin D (2014) Correlation of p16 status, hypoxic imaging using [18F]-misonidazole positron emission tomography and outcome in patients with loco-regionally advanced head and neck cancer. J Med Imaging Radiat Oncol 58:89-97
118. 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 63:5970-5977
119. Chitneni SK, Bida GT, Yuan H, Palmer GM, Hay MP, Melcher T, Wilson WR, Zalutsky MR, Dewhirst MW (2013) 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
120. Anderson RF, Yadav P, Patel D, Reynisson J, Tipparaju SR, Guise CP, Patterson AV, Denny WA, Maroz A, Shinde SS, Hay MP (2014) Characterisation of radicals formed by the triazine 1,4-dioxide hypoxia-activated prodrug, SN30000. Org Biomol Chem 12:3386-3392
121. Patterson AV, Silva S, Guise C, Abbattista M, Bull M, Hsu A, Sun J, Jung D, Grey A, Ashoorzadeh A, Anderson R, Smaill JB (2015) The hypoxia activated EGFR-TKI TH-4000 overcomes erlotinib-resistance in preclinical NSCLC models at plasma levels achieved in phase 1 clinical trial. Cancer Res 75: Abstract number 5358
122. Patterson AV, Silva S, Guise C, Bull M, Abbattista M, Hsu A, Sun JD, Hart CP, Pearce TE, Smaill JB (2015) TH-4000, a hypoxia-activated EGFR/Her2 inhibitor to treat EGFR-TKI resistant T790M-negative NSCLC. J Clin Oncol 33: abstract e13548
123. Cazares-Korner C, Pires IM, Swallow ID, Grayer SC, O'Connor LJ, Olcina MM, Christlieb M, Conway SJ, Hammond EM (2013) CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and Aurora A. ACS Chem Biol 8:1451-1459
124. Lindquist KE, Cran JD, Kordic K, Chua PC, Winters GC, Tan JS, Lozada J, Kyle AH, Evans JW, Minchinton AI (2013) Selective radiosensitization of hypoxic cells using BCCA621C: a novel hypoxia activated prodrug targeting DNA-dependent protein kinase. Tumour Microenvironment and Therapy 1:46-55
125. Zhu R, Baumann RP, Penketh PG, Shyam K, Sartorelli AC (2013) Hypoxia-selective O6-alkylguanine-DNA alkyltransferase inhibitors: design, synthesis, and evaluation of 6-(benzyloxy)-2-(aryldiazenyl)-9H-purines as prodrugs of O6-benzylguanine. J Med Chem 56:1355-1359
126. Karnthaler-Benbakka C, Groza D, Kryeziu K, Pichler V, Roller A, Berger W, Heffeter P, Kowol CR (2014) Tumor-targeting of EGFR inhibitors by hypoxia-mediated activation. Angew Chem Int Ed Engl 53:12930-12935
127. Perche F, Biswas S, Wang T, Zhu L, Torchilin VP (2014) Hypoxia-targeted siRNA delivery. Angew Chem Int Ed Engl 53:3362-3366
128. Karakashev SV, Reginato MJ (2015) Progress toward overcoming hypoxia-induced resistance to solid tumor therapy. Cancer Manag Res 7:253-264