Abstract
Hypoxia, which occurs in most cancer cases, disrupts the efficacy of anticarcinogens. Fortunately, hypoxia itself is a potential target for cancer treatment. Hypoxia-activated prodrugs (HAPs) can be selectively activated by reductase under hypoxia. Some promising HAPs have been already achieved, and many clinical trials of HAPs in different types of cancer are ongoing. However, none of them has been approved in clinic to date. From the studies on HAPs began, some achievements are obtained but more challenges are put forward. In this paper, we reviewed the research progress of HAPs to discuss the strategies for HAPs development. According to the research status and results of these studies, administration pattern, reductase activity, and patient selection need to be taken into consideration to further improve the efficacy of existing HAPs. As the requirement of new drug research and development, design of optimal preclinical models and clinical trials are quite important in HAPs development, while different drug delivery systems and anticancer drugs with different mechanisms can be sources of novel HAPs.
Keywords: Hypoxia-activated prodrug, topoisomerase II inhibitors, DNA alkylating agents, targeted drugs, reductase activity, patient selection.
Graphical Abstract
[1]
Wigerup C, Pahlman S, Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 2016; 164: 152-69.
[3]
Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011; 10(6): 417-27.
[4]
Cui J, Mao X, Olman V, Hastings PJ, Xu Y. Hypoxia and miscoupling between reduced energy efficiency and signaling to cell proliferation drive cancer to grow increasingly faster. J Mol Cell Biol 2012; 4(3): 174-6.
[5]
Vaupel P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 2008; 13(Suppl. 3): 21-6.
[6]
Janssen HL, Haustermans KM, Balm AJ, Begg AC. Hypoxia in head and neck cancer: how much, how important? Head Neck 2005; 27(7): 622-38.
[7]
Denny WA. The role of hypoxia-activated prodrugs in cancer therapy. Lancet Oncol 2000; 1(1): 25-9.
[8]
Zeman EM, Brown JM, Lemmon MJ, Hirst VK, Lee WWSR. -4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int J Radiat Oncol Biol Phys 1986; 12(7): 1239-42.
[9]
Patterson LH. Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent. Cancer Metastasis Rev 1993; 12(2): 119-34.
[10]
Foloppe N, Fisher LM, Howes R, et al. Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity. J Med Chem 2005; 48(13): 4332-45.
[11]
Anderson RF, Yadav P, Patel D, et al. Characterisation of radicals formed by the triazine 1,4-dioxide hypoxia-activated prodrug, SN30000. Org Biomol Chem 2014; 12(21): 3386-92.
[12]
Baran N, Konopleva M. Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy. Clin Cancer Res 2017; 23(10): 2382-90.
[13]
Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 2009; 9(5): 338-50.
[14]
Bailly C. Contemporary challenges in the design of topoisomerase II inhibitors for cancer chemotherapy. Chem Rev 2012; 112(7): 3611-40.
[15]
Zeman EM, Brown JM, Lemmon MJ, Hirst VK, Lee WWSR. -4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int J Radiat Oncol Biol Phys 1986; 12(7): 1239-42.
[16]
Rooseboom M, Commandeur JN, Vermeulen NP. Enzyme-catalyzed activation of anticancer prodrugs. Pharmacol Rev 2004; 56(1): 53-102.
[17]
Peters KB, Wang H, Brown JM, Iliakis G. Inhibition of DNA replication by tirapazamine. Cancer Res 2001; 61(14): 5425-31.
[18]
Peters KB, Brown JM. Tirapazamine: a hypoxia-activated topoisomerase II poison. Cancer Res 2002; 62(18): 5248-53.
[19]
Zhang J, Cao J, Weng Q, et al. Suppression of hypoxia-inducible factor 1alpha (HIF-1alpha) by tirapazamine is dependent on eIF2alpha phosphorylation rather than the mTORC1/4E-BP1 pathway. PloS One 2010; 5(11): e13910.
[20]
Le QT, Moon J, Redman M, et al. Phase II study of tirapazamine, cisplatin, and etoposide and concurrent thoracic radiotherapy for limited-stage small-cell lung cancer: SWOG 0222. J Clin Oncol 2009; 27(18): 3014-9.
[21]
Trinkaus ME, Hicks RJ, Young RJ, et al. 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 2014; 58(1): 89-97.
[22]
DiSilvestro PA, Ali S, Craighead PS, et al. 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 2014; 32(5): 458-64.
[23]
Miller VA, Ng KK, Grant SC, et al. 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 1997; 8: 1269-71.
[24]
Doherty N, Hancock SL, Kaye S, et al. Muscle cramping in phase i clinical trials of tirapazamine (SR 4233) with and without radiation. Int J Radiation Oncology Biol 1994; 29(2): 379-82.
[25]
Hicks KO, Pruijn FB, Sturman JR, Denny WA, Wilson WR. Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in HT29 multicellular layer cultures. Cancer Res 2003; 63(18): 5970-7.
[26]
Nishida CR, Lee M, de Montellano PR. Efficient hypoxic activation of the anticancer agent AQ4N by CYP2S1 and CYP2W1. Mol Pharmacol 2010; 78(3): 497-502.
[27]
Xiao Y, Shinkyo R, Guengerich FP. Cytochrome P450 2S1 is reduced by NADPH-cytochrome P450 reductase. Drug Metab Dispos 2011; 39(6): 944-6.
[28]
Nishida CR, Ortiz de Montellano PR. Reductive heme-dependent activation of the n-oxide prodrug AQ4N by nitric oxide synthase. J Med Chem 2008; 51(16): 5118-20.
[29]
Wilson WR, Denny WA, Pullen SM, et al. Tertiary amine N-oxides as bioreductive drugs_ DACA N-oxide, nitracrine N-oxide and AQ4N. Br J Cancer 1996; 74(Suppl. 27): S43-7.
[30]
Patterson LH, McKeown SR. AQ4N: a new approach to hypoxia-activated cancer chemotherapy. Br J Cancer 2000; 83(12): 1589-93.
[31]
Lalani AS, Alters SE, Wong A, et al. Selective tumor targeting by the hypoxia-activated prodrug AQ4N blocks tumor growth and metastasis in preclinical models of pancreatic cancer. Clin Cancer Res 2007; 13(7): 2216-25.
[32]
Ming L, Byrne NM, Camac SN, et al. Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumours: informed scheduling of the bioreductive drug AQ4N improves treatment response. Int J Cancer 2013; 132(6): 1323-32.
[33]
Gieling RG, Fitzmaurice RJ, Telfer BA, Babur M, Williams KJ. Dissemination via the lymphatic or angiogenic route impacts the pathology, microenvironment and hypoxia-related drug response of lung metastases. Clin Exp Metastasis 2015; 32(6): 567-77.
[34]
Patterson LH, McKeown SR, Ruparelia K, et al. Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. Br J Cancer 2000; 82(12): 1984-90.
[35]
Steward WP, Middleton M, Benghiat A, et al. 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 2007; 18(6): 1098-103.
[36]
Albertella MR, Loadman PM, Jones PH, et al. Hypoxia-selective targeting by the bioreductive prodrug AQ4N in patients with solid tumors: results of a phase I study. Clin Cancer Res 2008; 14(4): 1096-104.
[37]
Papadopoulos KP, Goel S, Beeram M, et al. A phase 1 open-label, accelerated dose-escalation study of the hypoxia-activated prodrug AQ4N in patients with advanced malignancies. Clin Cancer Res 2008; 14(21): 7110-5.
[38]
Williams KJ, Albertella MR, Fitzpatrick B, et al. In vivo activation of the hypoxia-targeted cytotoxin AQ4N in human tumor xenografts. Mol Cancer Ther 2009; 8(12): 3266-75.
[39]
Wang J, Guise CP, Dachs GU, et al. Identification of one-electron reductases that activate both the hypoxia prodrug SN30000 and diagnostic probe EF5. Biochem Pharmacol 2014; 91(4): 436-46.
[40]
Hunter FW, Young RJ, Shalev Z, et al. Identification of P450 Oxidoreductase as a Major Determinant of Sensitivity to Hypoxia-Activated Prodrugs. Cancer Res 2015; 75(19): 4211-23.
[41]
Wang J, Foehrenbacher A, Su J, et al. The 2-nitroimidazole EF5 is a biomarker for oxidoreductases that activate the bioreductive prodrug CEN-209 under hypoxia. Clin Cancer Res 2012; 18(6): 1684-95.
[42]
Hunter FW, Wang J, Patel R, et al. Homologous recombination repair-dependent cytotoxicity of the benzotriazine di-N-oxide CEN-209: comparison with other hypoxia-activated prodrugs. Biochem Pharmacol 2012; 83(5): 574-85.
[43]
Chan N, Koritzinsky M, Zhao H, et al. Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance. Cancer Res 2008; 68(2): 605-14.
[44]
Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer 2012; 12(2): 104-20.
[45]
Relevance of N-nitroso compounds to human cancer: exposures and mechanisms. Proceedings of the IXth International Symposium on N-Nitroso Compounds. Baden, Austria, 1-5 September 1986. IARC Sci Publ 1987; (84): 1-663.
[46]
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; 856(1-2): 302-11.
[47]
Patterson AV, Ferry DM, Edmunds SJ, et al. Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent PR-104. Clin Cancer Res 2007; 13(13): 3922-32.
[48]
Singleton RS, Guise CP, Ferry DM, 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; 69(9): 3884-91.
[49]
Guise CP, Wang AT, Theil A, et al. Identification of human reductases that activate the dinitrobenzamide mustard prodrug PR-104A: a role for NADPH:cytochrome P450 oxidoreductase under hypoxia. Biochem Pharmacol 2007; 74(6): 810-20.
[50]
Jameson MB, Rischin D, Pegram M, 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; 65(4): 791-801.
[51]
McKeage MJ, Gu Y, Wilson WR, et al. A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients. BMC Cancer 2011; 11: 432.
[52]
McKeage MJ, Jameson MB, Ramanathan RK, et al. PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours. BMC Cancer 2012; 12: 496.
[53]
Konopleva MTP, Yi CA, Borthakur G, et al. Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia. Haematologica 2015; 100(7): 927-34.
[54]
Abou-Alfa GK, Chan SL, Lin CC, et al. PR-104 plus sorafenib in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2011; 68(2): 539-45.
[55]
Moradi Manesh D, El-Hoss J, Evans K, et al. AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. Blood 2015; 126(10): 1193-202.
[56]
Jamieson SM, Gu Y, Manesh DM, et al. A novel fluorometric assay for aldo-keto reductase 1C3 predicts metabolic activation of the nitrogen mustard prodrug PR-104A in human leukaemia cells. Biochem Pharmacol 2014; 88(1): 36-45.
[57]
Guise CP, Abbattista MR, Singleton RS, et al. The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3. Cancer Res 2010; 70(4): 1573-84.
[58]
Mowday AM, Ashoorzadeh A, Williams EM, et al. Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy. Biochem Pharmacol 2016; 116: 176-87.
[59]
Duan JX, Jiao H, Kaizerman J, et al. Steve Ammons, Charles P. Hart, Mark Matteucci. Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs. J Med Chem 2008; 51: 2412-20.
[60]
Meng F, Evans JW, Bhupathi D, et al. Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. Mol Cancer Ther 2012; 11(3): 740-51.
[61]
Charles P. Hart FM, Monica Banica, James Evans, et al. In vitro activity profile of the novel hypoxia-activated cytotoxic prodrug TH-302. Cancer Res 2008; 1441.
[62]
Hunter FW, Hsu HL, Su J, et al. Dual targeting of hypoxia and homologous recombination repair dysfunction in triple-negative breast cancer. Mol Cancer Ther 2014; 13(11): 2501-14.
[63]
Portwood S, Lal D, Hsu YC, et al. Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models. Clin Cancer Res 2013; 19(23): 6506-19.
[64]
Weiss GJ, Lewandowski K, Oneall J, Kroll S. Resolution of Cullen’s sign in patient with metastatic melanoma responding to hypoxia-activated prodrug TH-302. Dermatol Rep 2011; 3(3): e56.
[65]
Weiss GJ, Infante JR, Chiorean EG, et al. 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 2011; 17(9): 2997-3004.
[66]
Hu J, Handisides DR, Van Valckenborgh E, et al. Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug. Blood 2010; 116(9): 1524-7.
[67]
Hu J, Van Valckenborgh E, Xu D, et al. Synergistic induction of apoptosis in multiple myeloma cells by bortezomib and hypoxia-activated prodrug TH-302, in vivo and in vitro. Mol Cancer Ther 2013; 12(9): 1763-73.
[68]
Liu Q, Sun JD, Wang J, et al. TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules. Cancer Chemother Pharmacol 2012; 69(6): 1487-98.
[69]
Borad MJ, Reddy SG, Bahary N, et al. Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer. J Clin Oncol 2015; 33(13): 1475-81.
[70]
Chawla SP, Cranmer LD, Van Tine BA, et al. 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 2014; 32(29): 3299-306.
[71]
Merck Decides Not to Pursue Evofosfamide Further in Soft Tissue Sarcoma and Pancreatic Cancer Merk Group2015 [cited 2016 April 10]. Available from:. http://www.merckgroup.com
[72]
Lohse I, Rasowski J, Cao P, et al. Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302. Oncotarget 2016; 7(23): 33571-80.
[73]
Nytko KJ, Grgic I, Bender S, et al. The hypoxia-activated prodrug evofosfamide in combination with multiple regimens of radiotherapy. Oncotarget 2017; 8(14): 23702-12.
[74]
Riedel RF, Meadows KL, Lee PH, et al. Phase I study of pazopanib plus TH-302 in advanced solid tumors. Cancer Chemother Pharmacol 2017; 79(3): 611-9.
[75]
Laubach JP, Liu CJ, Raje NS, et al. A Phase 1/2 Study of evofosfamide, A Hypoxia-Activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma. Clin Cancer Res 2018.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-1325]
[http://dx.doi.org/10.1158/1078-0432.CCR-18-1325]
[76]
Victoria J, Shevan S, Maria A, et al. Preclinical Rationale for the Ongoing Phase 2 Study of the Hypoxia-Activated EGFR-TKI Tarloxotinib Bromide (TH-4000) in Patients with Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN) or Skin (SCCS). AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference 2015.
[77]
Shibata T, Giaccia AJ, Brown JM. Hypoxia-inducible regulation of a prodrug-activating enzyme for tumor-specific gene therapy. Neoplasia 2002; 4(1): 40-8.
[78]
Ramaekers CH, van den Beucken T, Meng A, et al. Hypoxia disrupts the Fanconi anemia pathway and sensitizes cells to chemotherapy through regulation of UBE2T. Radiother Oncol 2011; 101(1): 190-7.
[79]
Stevenson RJ, Denny WA, Tercel M, Pruijn FB, Ashoorzadeh A. Nitro seco analogues of the duocarmycins containing sulfonate leaving groups as hypoxia-activated prodrugs for cancer therapy. J Med Chem 2012; 55(6): 2780-802.
[80]
Wojtkowiak JW, Cornnell HC, Matsumoto S, et al. Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302. Cancer Metab 2015; 3(1): 2.
[81]
Abbattista MR, Jamieson SM, Gu Y, et al. Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma. Cancer Biol Ther 2015; 16(4): 610-22.
[82]
Lu L, Wang M, Mao Z, et al. A novel dinuclear iridium(III) complex as a G-quadruplex-selective probe for the luminescent switch-on detection of transcription factor HIF-1alpha. Sci Rep 2016; 6: 22458.
[83]
Beall HD, Winski SI. Mechanisms of action of quinone-containing alkylating agents. I: NQO1-directed drug development. Front Biosci 2000; 5: D639-48.
[84]
Cummings J, Spanswick VJ, Gardiner J, Ritchie A, Smyth JF. Pharmacological and biochemical determinants of the antitumour activity of the indoloquinone EO9. Biochem Pharmacol 1998; 55: 253-60.
[85]
Hong Y, Chia YM, Yeo RH, et al. Inactivation of Human Cytochrome P450 3A4 and 3A5 by Dronedarone and N-Desbutyl Dronedarone. Mol Pharmacol 2016; 89(1): 1-13.
[86]
Guan DX, Shi J, Zhang Y, et al. Sorafenib enriches epithelial cell adhesion molecule-positive tumor initiating cells and exacerbates a subtype of hepatocellular carcinoma through TSC2-AKT cascade. Hepatology 2015; 62(6): 1791-803.
[87]
Nesbitt H, Byrne NM, Williams SN, et al. Targeting hypoxic prostate tumours using the novel hypoxia-activated prodrug OCT1002 inhibits expression of genes associated with malignant progression. Clin Cancer Res 2017; 23(7): 1797-808.
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