Radiation Oncology Journal

The Korean Society for Radiation Oncology (대한방사선종양학회)
권호 표지
DOI QR코드

DOI QR Code

Tumor hypoxia and reoxygenation: the yin and yang for radiotherapy

  • Hong, Beom-Ju (Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology) ;
  • Kim, Jeongwoo (Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology) ;
  • Jeong, Hoibin (Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology) ;
  • Bok, Seoyeon (Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology) ;
  • Kim, Young-Eun (Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology) ;
  • Ahn, G-One (Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology)
  • Received : 2016.11.01
  • Accepted : 2016.12.12
  • Published : 2016.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Tumor hypoxia, a common feature occurring in nearly all human solid tumors is a major contributing factor for failures of anticancer therapies. Because ionizing radiation depends heavily on the presence of molecular oxygen to produce cytotoxic effect, the negative impact of tumor hypoxia had long been recognized. In this review, we will highlight some of the past attempts to overcome tumor hypoxia including hypoxic radiosensitizers and hypoxia-selective cytotoxin. Although they were (still are) a very clever idea, they lacked clinical efficacy largely because of 'reoxygenation' phenomenon occurring in the conventional low dose hyperfractionation radiotherapy prevented proper activation of these compounds. Recent meta-analysis and imaging studies do however indicate that there may be a significant clinical benefit in lowering the locoregional failures by using these compounds. Latest technological advancement in radiotherapy has allowed to deliver high doses of radiation conformally to the tumor volume. Although this technology has brought superb clinical responses for many types of cancer, recent modeling studies have predicted that tumor hypoxia is even more serious because 'reoxygenation' is low thereby leaving a large portion of hypoxic tumor cells behind. Wouldn't it be then reasonable to combine hypoxic radiosensitizers and/or hypoxia-selective cytotoxin with the latest radiotherapy? We will provide some preclinical and clinical evidence to support this idea hoping to revamp an enthusiasm for hypoxic radiosensitizers or hypoxia-selective cytotoxins as an adjunct therapy for radiotherapy.

Keywords

References

  1. Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 1955;9:539-49. https://doi.org/10.1038/bjc.1955.55
  2. Brown JM. Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Br J Radiol 1979;52:650-6. https://doi.org/10.1259/0007-1285-52-620-650
  3. Nozue M, Lee I, Yuan F, et al. Interlaboratory variation in oxygen tension measurement by Eppendorf "Histograph" and comparison with hypoxic marker. J Surg Oncol 1997;66:30-8. https://doi.org/10.1002/(SICI)1096-9098(199709)66:1<30::AID-JSO7>3.0.CO;2-O
  4. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004;4:437-47. https://doi.org/10.1038/nrc1367
  5. Li XF, Carlin S, Urano M, Russell J, Ling CC, O'Donoghue JA. Visualization of hypoxia in microscopic tumors by immunofluorescent microscopy. Cancer Res 2007;67:7646-53. https://doi.org/10.1158/0008-5472.CAN-06-4353
  6. Brizel DM, Scully SP, Harrelson JM, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 1996;56:941-3.
  7. Hammond EM, Giaccia AJ. Hypoxia-inducible factor-1 and p53: friends, acquaintances, or strangers? Clin Cancer Res 2006;12:5007-9. https://doi.org/10.1158/1078-0432.CCR-06-0613
  8. Jeong H, Bok S, Hong BJ, Choi HS, Ahn GO. Radiation-induced immune responses: mechanisms and therapeutic perspectives. Blood Res 2016;51:157-63. https://doi.org/10.5045/br.2016.51.3.157
  9. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677-704. https://doi.org/10.1146/annurev.immunol.26.021607.090331
  10. Noman MZ, Desantis G, Janji B, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 2014;211:781-90. https://doi.org/10.1084/jem.20131916
  11. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992;12:5447-54. https://doi.org/10.1128/MCB.12.12.5447
  12. Dische S. Local tumour control and its effect upon survival of the patient. Australas Radiol 1983;27:181-5. https://doi.org/10.1111/j.1440-1673.1983.tb02431.x
  13. Chaplin DJ, Durand RE, Stratford IJ, Jenkins TC. The radiosensitizing and toxic effects of RSU-1069 on hypoxic cells in a murine tumor. Int J Radiat Oncol Biol Phys 1986;12:1091-5. https://doi.org/10.1016/0360-3016(86)90233-6
  14. Rockwell S. Oxygen delivery: implications for the biology and therapy of solid tumors. Oncol Res 1997;9:383-90.
  15. Hoskin PJ, Rojas AM, Bentzen SM, Saunders MI. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. J Clin Oncol 2010;28:4912-8. https://doi.org/10.1200/JCO.2010.28.4950
  16. Riess JG. Understanding the fundamentals of perfluorocarbons and perfluorocarbon emulsions relevant to in vivo oxygen delivery. Artif Cells Blood Substit Immobil Biotechnol 2005;33:47-63. https://doi.org/10.1081/BIO-200046659
  17. Sun X, Xing L, Ling CC, Li GC. The effect of mild temperature hyperthermia on tumour hypoxia and blood perfusion: relevance for radiotherapy, vascular targeting and imaging. Int J Hyperthermia 2010;26:224-31. https://doi.org/10.3109/02656730903479855
  18. Adams GE, Cooke MS. Electron-affinic sensitization. I: A structural basis for chemical radiosensitizers in bacteria. Int J Radiat Biol Relat Stud Phys Chem Med 1969;15:457-71. https://doi.org/10.1080/09553006914550741
  19. Dische S. Chemical sensitizers for hypoxic cells: a decade of experience in clinical radiotherapy. Radiother Oncol 1985;3:97-115. https://doi.org/10.1016/S0167-8140(85)80015-3
  20. Ahn GO, Brown M. Targeting tumors with hypoxia-activated cytotoxins. Front Biosci 2007;12:3483-501. https://doi.org/10.2741/2329
  21. Dische S, Saunders MI, Lee ME, Adams GE, Flockhart IR. Clinical testing of the radiosensitizer Ro 07-0582: experience with multiple doses. Br J Cancer 1977;35:567-79. https://doi.org/10.1038/bjc.1977.90
  22. Brown JM, Yu NY, Brown DM, Lee WW. SR-2508: a 2-nitroimidazole amide which should be superior to misonidazole as a radiosensitizer for clinical use. Int J Radiat Oncol Biol Phys 1981;7:695-703. https://doi.org/10.1016/0360-3016(81)90460-0
  23. Saunders MI, Anderson PJ, Bennett MH, et al. The clinical testing of Ro 03-8799: pharmacokinetics, toxicology, tissue and tumor concentrations. Int J Radiat Oncol Biol Phys 1984;10:1759-63. https://doi.org/10.1016/0360-3016(84)90544-3
  24. Coleman CN, Hirst VK, Brown DM, Halsey J. The effect of vitamin B6 on the neurotoxicity and pharmacology of desmethylmisonidazole and misonidazole: clinical and laboratory studies. Int J Radiat Oncol Biol Phys 1984;10:1381-6. https://doi.org/10.1016/0360-3016(84)90353-5
  25. Lee DJ, Cosmatos D, Marcial VA, et al. Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas. Int J Radiat Oncol Biol Phys 1995;32:567-76. https://doi.org/10.1016/0360-3016(95)00150-W
  26. Smithen CE, Clarke ED, Dale JA, et al. Novel (nitro-1-imidazolyl) alkanolamines as potential radiosensitisers with improved therapeutic properties. In: Brady LW, editor. Radiation sensitizers: their use in the clinical management of cancer. New York: Masson Publishing Inc.; 1980. p. 22-32.
  27. Dische S, Machin D, Chassange D. A trial of Ro 03-8799 (pimonidazole) in carcinoma of the uterine cervix: an interim report from the Medical Research Council Working Party on advanced carcinoma of the cervix. Radiother Oncol 1993;26:93-103. https://doi.org/10.1016/0167-8140(93)90089-Q
  28. Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck: a systematic review and meta-analysis. Radiother Oncol 2011;100:22-32. https://doi.org/10.1016/j.radonc.2011.03.004
  29. Rischin D, Peters LJ, O'Sullivan B, et al. 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 2010;28:2989-95. https://doi.org/10.1200/JCO.2009.27.4449
  30. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011;11:393-410. https://doi.org/10.1038/nrc3064
  31. Arteel GE, Thurman RG, Raleigh JA. Reductive metabolism of the hypoxia marker pimonidazole is regulated by oxygen tension independent of the pyridine nucleotide redox state. Eur J Biochem 1998;253:743-50. https://doi.org/10.1046/j.1432-1327.1998.2530743.x
  32. Karasawa K, Sunamura M, Okamoto A, et al. Efficacy of novel hypoxic cell sensitiser doranidazole in the treatment of locally advanced pancreatic cancer: long-term results of a placebocontrolled randomised study. Radiother Oncol 2008;87:326-30. https://doi.org/10.1016/j.radonc.2008.02.007
  33. Brown JM. The hypoxic cell: a target for selective cancer therapy: eighteenth Bruce F. Cain Memorial Award lecture. Cancer Res 1999;59:5863-70.
  34. Marcu L, Olver I. Tirapazamine: from bench to clinical trials. Curr Clin Pharmacol 2006;1:71-9. https://doi.org/10.2174/157488406775268192
  35. Fleming IN, Manavaki R, Blower PJ, et al. Imaging tumour hypoxia with positron emission tomography. Br J Cancer 2015;112:238-50. https://doi.org/10.1038/bjc.2014.610
  36. Rischin D, Hicks RJ, Fisher R, et al. 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 2006;24:2098-104. https://doi.org/10.1200/JCO.2005.05.2878
  37. Dewhirst MW. Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress. Radiat Res 2009;172:653-65. https://doi.org/10.1667/RR1926.1
  38. Lin Z, Mechalakos J, Nehmeh S, et al. The influence of changes in tumor hypoxia on dose-painting treatment plans based on 18F-FMISO positron emission tomography. Int J Radiat Oncol Biol Phys 2008;70:1219-28. https://doi.org/10.1016/j.ijrobp.2007.09.050
  39. Connell PP, Hellman S. Advances in radiotherapy and implications for the next century: a historical perspective. Cancer Res 2009;69:383-92. https://doi.org/10.1158/0008-5472.CAN-07-6871
  40. Kallman RF. The phenomenon of reoxygenation and its implications for fractionated radiotherapy. Radiology 1972;105:135-42. https://doi.org/10.1148/105.1.135
  41. Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48:7-16. https://doi.org/10.1016/S0360-3016(00)00663-5
  42. Timmerman RD. Surgery versus stereotactic body radiation therapy for early-stage lung cancer: who's down for the count? J Clin Oncol 2010;28:907-9. https://doi.org/10.1200/JCO.2009.26.5165
  43. Carlson DJ, Keall PJ, Loo BW Jr, Chen ZJ, Brown JM. Hypofractionation results in reduced tumor cell kill compared to conventional fractionation for tumors with regions of hypoxia. Int J Radiat Oncol Biol Phys 2011;79:1188-95. https://doi.org/10.1016/j.ijrobp.2010.10.007
  44. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303:1070-6. https://doi.org/10.1001/jama.2010.261
  45. Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys 2005;63:1427-31. https://doi.org/10.1016/j.ijrobp.2005.05.034
  46. Chang JY, Balter PA, Dong L, et al. Stereotactic body radiation therapy in centrally and superiorly located stage I or isolated recurrent non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;72:967-71. https://doi.org/10.1016/j.ijrobp.2008.08.001
  47. Song C, Hong BJ, Bok S, et al. Real-time tumor oxygenation changes after single high-dose radiation therapy in orthotopic and subcutaneous lung cancer in mice: clinical implication for stereotactic ablative radiation therapy schedule optimization. Int J Radiat Oncol Biol Phys 2016;95:1022-31. https://doi.org/10.1016/j.ijrobp.2016.01.064
  48. Kelada OJ, Decker RH, Zheng MQ, et al. Quantification of tumor hypoxia in lung cancer patients undergoing stereotactic body radiotherapy using dynamic PET imaging. In: 15th International Congress of Radiation Research (ICRR) Annual Meeting; 2015 May 25-29; Kyoto, Japan.
  49. Siemann DW, Hill SA. Increased therapeutic benefit through the addition of misonidazole to a nitrosourea-radiation combination. Cancer Res 1986;46:629-32.
  50. Rofstad EK. Radiation response of the cells of a human malignant melanoma xenograft. Effect of hypoxic cell radiosensitizers. Radiat Res 1981;87:670-83. https://doi.org/10.2307/3575529
  51. Palcic B, Faddegon B, Skarsgard LD. The effect of misonidazole as a hypoxic radiosensitizer at low dose. Radiat Res 1984;100:340-7. https://doi.org/10.2307/3576355
  52. Wittenborn TR, Horsman MR. Targeting tumour hypoxia to improve outcome of stereotactic radiotherapy. Acta Oncol 2015;54:1385-92. https://doi.org/10.3109/0284186X.2015.1064162
  53. Nori D, Cain JM, Hilaris BS, Jones WB, Lewis JL Jr. Metronidazole as a radiosensitizer and high-dose radiation in advanced vulvovaginal malignancies, a pilot study. Gynecol Oncol 1983;16:117-28. https://doi.org/10.1016/0090-8258(83)90017-3
  54. Schlaff CD, Krauze A, Belard A, O'Connell JJ, Camphausen KA. Bringing the heavy: carbon ion therapy in the radiobiological and clinical context. Radiat Oncol 2014;9:88. https://doi.org/10.1186/1748-717X-9-88
  55. Schuler E, Trovati S, King G, et al. Experimental platform for ultra-high dose rate FLASH irradiation of small animals using a clinical linear accelerator. Int J Radiat Oncol Biol Phys 2016 Sep 20. [Epub]. http://dx.doi.org/10.1016/j.ijrobp.2016.09.018.
  56. Favaudon V, Caplier L, Monceau V, et al. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci Transl Med 2014;6:245ra93. https://doi.org/10.1126/scitranslmed.3008973
  57. Palmer GM, Vishwanath K, Dewhirst MW. Application of optical imaging and spectroscopy to radiation biology. Radiat Res 2012;177:365-75. https://doi.org/10.1667/RR2531.1
  58. Vishwanath K, Klein D, Chang K, Schroeder T, Dewhirst MW, Ramanujam N. Quantitative optical spectroscopy can identify long-term local tumor control in irradiated murine head and neck xenografts. J Biomed Opt 2009;14:054051. https://doi.org/10.1117/1.3251013
  59. Park J, Lee J, Kwag J, et al. quantum dots in an amphiphilic polyethyleneimine derivative platform for cellular labeling, targeting, gene delivery, and ratiometric oxygen sensing. ACS Nano 2015;9:6511-21. https://doi.org/10.1021/acsnano.5b02357
  60. Kersey FR, Zhang G, Palmer GM, Dewhirst MW, Fraser CL. Stereocomplexed poly(lactic acid)-poly(ethylene glycol) nanoparticles with dual-emissive boron dyes for tumor accumulation. ACS Nano 2010;4:4989-96. https://doi.org/10.1021/nn901873t
  61. Spencer JA, Ferraro F, Roussakis E, et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 2014;508:269-73. https://doi.org/10.1038/nature13034
  62. Prasad P, Gordijo CR, Abbasi AZ, et al. Multifunctional albumin-MnO(2) nanoparticles modulate solid tumor microenvironment by attenuating hypoxia, acidosis, vascular endothelial growth factor and enhance radiation response. ACS Nano 2014;8:3202-12. https://doi.org/10.1021/nn405773r
  63. Song X, Feng L, Liang C, Yang K, Liu Z. Ultrasound triggered tumor oxygenation with oxygen-shuttle nanoperfluorocarbon to overcome hypoxia-associated resistance in cancer therapies. Nano Lett 2016;16:6145-53. https://doi.org/10.1021/acs.nanolett.6b02365

Cited by

  1. Mechanism of the Antitumor and Radiosensitizing Effects of a Manganese Porphyrin, MnHex-2-PyP vol.27, pp.14, 2016, https://doi.org/10.1089/ars.2016.6889
  2. Harnessing the Power of Nanotechnology for Enhanced Radiation Therapy vol.11, pp.6, 2016, https://doi.org/10.1021/acsnano.7b03675
  3. Poly-(ADP-ribose)-polymerase inhibitors as radiosensitizers: a systematic review of pre-clinical and clinical human studies vol.8, pp.40, 2016, https://doi.org/10.18632/oncotarget.19079
  4. Strahlentherapie bei Weichteilsarkomen der Extremitäten : Ihre Rolle in der multimodalen Behandlung vol.20, pp.1, 2018, https://doi.org/10.1007/s10039-017-0305-3
  5. Hierarchical Multiplexing Nanodroplets for Imaging-Guided Cancer Radiotherapy via DNA Damage Enhancement and Concomitant DNA Repair Prevention vol.12, pp.6, 2016, https://doi.org/10.1021/acsnano.8b01508
  6. Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases vol.6, pp.None, 2016, https://doi.org/10.3389/fchem.2018.00027
  7. Harnessing Tumor Microenvironment for Nanoparticle-Mediated Radiotherapy vol.1, pp.5, 2016, https://doi.org/10.1002/adtp.201800050
  8. Gas Therapy: An Emerging “Green” Strategy for Anticancer Therapeutics vol.1, pp.6, 2016, https://doi.org/10.1002/adtp.201800084
  9. The presumed MTH1-inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia vol.18, pp.None, 2018, https://doi.org/10.1186/s12885-018-5095-x
  10. Ultralong circulating choline phosphate liposomal nanomedicines for cascaded chemo-radiotherapy vol.7, pp.4, 2016, https://doi.org/10.1039/c9bm00051h
  11. Tumor Reoxygenation and Blood Perfusion Enhanced Photodynamic Therapy using Ultrathin Graphdiyne Oxide Nanosheets vol.19, pp.6, 2016, https://doi.org/10.1021/acs.nanolett.9b01458
  12. Reactive oxygen species and cancer: A complex interaction vol.452, pp.None, 2016, https://doi.org/10.1016/j.canlet.2019.03.020
  13. Enhancing the efficacy of immunotherapy using radiotherapy vol.9, pp.9, 2020, https://doi.org/10.1002/cti2.1169
  14. State-of-the-art iron-based nanozymes for biocatalytic tumor therapy vol.5, pp.2, 2020, https://doi.org/10.1039/c9nh00577c
  15. The Role of Hypoxia and SRC Tyrosine Kinase in Glioblastoma Invasiveness and Radioresistance vol.12, pp.10, 2020, https://doi.org/10.3390/cancers12102860
  16. Nanomaterials to relieve tumor hypoxia for enhanced photodynamic therapy vol.35, pp.None, 2016, https://doi.org/10.1016/j.nantod.2020.100960
  17. Mechanisms for Tuning Engineered Nanomaterials to Enhance Radiation Therapy of Cancer vol.7, pp.24, 2016, https://doi.org/10.1002/advs.202003584
  18. Reactive Oxygen Species: Beyond Their Reactive Behavior vol.46, pp.1, 2016, https://doi.org/10.1007/s11064-020-03208-7
  19. The regulation of immune checkpoints by the hypoxic tumor microenvironment vol.9, pp.None, 2016, https://doi.org/10.7717/peerj.11306
  20. Effect of spatial distribution of boron and oxygen concentration on DNA damage induced from boron neutron capture therapy using Monte Carlo simulations vol.97, pp.7, 2016, https://doi.org/10.1080/09553002.2021.1928785