Seminars in Nuclear Medicine
Volume 38, Issue 2 , Pages 119-128 , March 2008

Fundamentals of Molecular Imaging: Rationale and Applications With Relevance for Radiation Oncology

  • Heiko Schöder, MD

      Affiliations

    • Department of Radiology/Nuclear Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.
    • Corresponding Author InformationAddress reprint requests to Heiko Schöder, MD, Department of Radiology/Nuclear Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 77, New York, NY 10021.
    • ,
  • Seng Chuan Ong, MD

      Affiliations

    • Department of Nuclear Medicine and PET, Singapore General Hospital, Singapore.

References 

  1. Massoud TF, Gambhir SS. Molecular imaging in living subjects: Seeing fundamental biological processes in a new light. Genes Dev. 2003;17:545–580
  2. Ling CC, Humm J, Larson S, et al. Towards multidimensional radiotherapy (MD-CRT): Biological imaging and biological conformality. Int J Radiat Oncol Biol Phys. 2000;47:551–560
  3. Groves AM, Win T, Haim SB, Ell PJ. Non-[18F]FDG PET in clinical oncology. Lancet Oncol. 2007;8:822–830
  4. Kelloff GJ, Krohn KA, Larson SM, et al. The progress and promise of molecular imaging probes in oncologic drug development. Clin Cancer Res. 2005;11:7967–7985
  5. Hammoud DA, Hoffman JM, Pomper MG. Molecular neuroimaging: From conventional to emerging techniques. Radiology. 2007;245:21–42
  6. Hamstra DA, Rehemtulla A, Ross BD. Diffusion magnetic resonance imaging: A biomarker for treatment response in oncology. J Clin Oncol. 2007;25:4104–4109
  7. Wu JC, Bengel FM, Gambhir SS. Cardiovascular molecular imaging. Radiology. 2007;244:337–355
  8. Weissleder R, Mahmood U. Molecular imaging. Radiology. 2001;219:316–333
  9. Czernin J, Weber WA, Herschman HR. Molecular imaging in the development of cancer therapeutics. Annu Rev Med. 2006;57:99–118
  10. Gambhir SS. Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer. 2002;2:683–693
  11. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70
  12. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis?. Nat Rev Cancer. 2004;4:891–899
  13. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7:763–777
  14. Glunde K, Jie C, Bhujwalla ZM. Molecular causes of the aberrant choline phospholipid metabolism in breast cancer. Cancer Res. 2004;64:4270–4276
  15. Warburg O. The Metabolism of Tumors. New York, NY: Richard R. Smith; 1931;
  16. Warburg O, Posener K, Negelein E. The metabolism of the carcinoma cell. Biochem Zeitschrift. 1924;152:319–344
  17. Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202:654–662
  18. Weber G. Enzymology of cancer cells (second of two parts). N Engl J Med. 1977;296:541–551
  19. Weber G. Enzymology of cancer cells (first of two parts). N Engl J Med. 1977;296:486–492
  20. Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med. 2004;10:594–601
  21. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–732
  22. Lum J, Bui T, Gruber M, et al. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev. 2007;21:1037–1049
  23. Elstrom RL, Bauer DE, Buzzai M, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004;64:3892–3899
  24. Bui T, Thompson CB. Cancer’s sweet tooth. Cancer cell. 2006;9:419–420
  25. Mac Manus MP, Hicks RJ, Matthews JP, et al. High rate of detection of unsuspected distant metastases by PET in apparent Stage III non-small-cell lung cancer: Implications for radical radiation therapy. Int J Radiat Oncol Biol Phys. 2001;50:287–293
  26. Bradley J, Thorstad WL, Mutic S, et al. Impact of FDG-PET on radiation therapy volume delineation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2004;59:78–86
  27. Erdi YE, Rosenzweig K, Erdi AK, et al. Radiotherapy treatment planning for patients with non-small cell lung cancer using positron emission tomography (PET). Radiother Oncol. 2002;62:51–60
  28. Nestle U, Walter K, Schmidt S, et al. 18F-deoxyglucose positron emission tomography (FDG-PET) for the planning of radiotherapy in lung cancer: High impact in patients with atelectasis. Int J Radiat Oncol Biol Phys. 1999;44:593–597
  29. Vanuytsel LJ, Vansteenkiste JF, Stroobants SG, et al. The impact of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer. Radiother Oncol. 2000;55:317–324
  30. Ciernik IF, Dizendorf E, Baumert BG, et al. Radiation treatment planning with an integrated positron emission and computer tomography (PET/CT): A feasibility study. Int J Radiat Oncol Biol Phys. 2003;57:853–863
  31. Leong T, Everitt C, Yuen K, et al. A prospective study to evaluate the impact of FDG-PET on CT-based radiotherapy treatment planning for oesophageal cancer. Radiother Oncol. 2006;78:254–261
  32. De Ruysscher D, Wanders S, Minken A, et al. Effects of radiotherapy planning with a dedicated combined PET-CT-simulator of patients with non-small cell lung cancer on dose limiting normal tissues and radiation dose-escalation: A planning study. Radiother Oncol. 2005;77:5–10
  33. Heron DE, Andrade RS, Flickinger J, et al. Hybrid PET-CT simulation for radiation treatment planning in head-and-neck cancers: A brief technical report. Int J Radiat Oncol Biol Phys. 2004;60:1419–1424
  34. Grills IS, Yan D, Black QC, Wong CY, Martinez AA, Kestin LL. Clinical implications of defining the gross tumor volume with combination of CT and 18FDG-positron emission tomography in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2007;67:709–719
  35. Moureau-Zabotto L, Touboul E, Lerouge D, et al. Impact of CT and 18F-deoxyglucose positron emission tomography image fusion for conformal radiotherapy in esophageal carcinoma. Int J Radiat Oncol Biol Phys. 2005;63:340–345
  36. Geets X, Daisne JF, Tomsej M, Duprez T, Lonneux M, Gregoire V. Impact of the type of imaging modality on target volumes delineation and dose distribution in pharyngo-laryngeal squamous cell carcinoma: Comparison between pre- and per-treatment studies. Radiother Oncol. 2006;78:291–297
  37. Madani I, Duthoy W, Derie C, et al. Positron emission tomography-guided, focal-dose escalation using intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys. 2007;68:126–135
  38. Ashamalla H, Rafla S, Parikh K, et al. The contribution of integrated PET/CT to the evolving definition of treatment volumes in radiation treatment planning in lung cancer. Int J Radiat Oncol Biol Phys. 2005;63:1016–1023
  39. Mac Manus MP, Hicks RJ, Matthews JP, et al. Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol. 2003;21:1285–1292
  40. Grigsby PW, Siegel BA, Dehdashti F, Mutch DG. Posttherapy surveillance monitoring of cervical cancer by FDG-PET. Int J Radiat Oncol Biol Phys. 2003;55:907–913
  41. Medes G, Thomas A, Weinhouse S. Metabolism of neoplastic tissue (IV. A study of lipid synthesis in neoplastic tissue slices in vitro). Cancer Res. 1953;13:27–29
  42. Kuhajda FP. Fatty acid synthase and cancer: New application of an old pathway. Cancer Res. 2006;66:5977–5980
  43. Kuhajda FP, Jenner K, Wood FD, et al. Fatty acid synthesis: A potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA. 1994;91:6379–6383
  44. Shah US, Dhir R, Gollin SM, et al. Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma. Hum Pathol. 2006;37:401–409
  45. Swinnen JV, Roskams T, Joniau S, et al. Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int J Cancer. 2002;98:19–22
  46. Swinnen JV, Heemers H, Deboel L, Foufelle F, Heyns W, Verhoeven G. Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway. Oncogene. 2000;19:5173–5181
  47. Porstmann T, Griffiths B, Chung YL, et al. PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene. 2005;24:6465–6481
  48. Bandyopadhyay S, Pai SK, Watabe M, et al. FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis. Oncogene. 2005;24:5389–5395
  49. Van de Sande T, De Schrijver E, Heyns W, Verhoeven G, Swinnen JV. Role of the phosphatidylinositol 3′-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Cancer Res. 2002;62:642–646
  50. Swinnen JV, Ulrix W, Heyns W, Verhoeven G. Coordinate regulation of lipogenic gene expression by androgens: Evidence for a cascade mechanism involving sterol regulatory element binding proteins. Proc Natl Acad Sci USA. 1997;94:12975–12980
  51. Graner E, Tang D, Rossi S, et al. The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer cell. 2004;5:253–261
  52. Menendez JA, Vellon L, Colomer R, Lupu R. Pharmacological and small interference RNA-mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) synergistically enhances Taxol (paclitaxel)-induced cytotoxicity. Int J Cancer. 2005;115:19–35
  53. Bandyopadhyay S, Zhan R, Wang Y, et al. Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells. Cancer Res. 2006;66:5934–5940
  54. Hernandez-Alcoceba R, Saniger L, Campos J, et al. Choline kinase inhibitors as a novel approach for antiproliferative drug design. Oncogene. 1997;15:2289–2301
  55. Ramirez de Molina A, Gutierrez R, Ramos MA, et al. Increased choline kinase activity in human breast carcinomas: Clinical evidence for a potential novel antitumor strategy. Oncogene. 2002;21:4317–4322
  56. Ramirez de Molina A, Rodriguez-Gonzalez A, Gutierrez R, et al. Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers. Biochem Biophys Res Commun. 2002;296:580–583
  57. Ackerstaff E, Glunde K, Bhujwalla ZM. Choline phospholipid metabolism: A target in cancer cells?. J Cell Biochem. 2003;90:525–533
  58. Ackerstaff E, Pflug BR, Nelson JB, et al. Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells. Cancer Res. 2001;61:3599–3603
  59. Hara T. 11C choline and 2-deoxy-2-[18F]fluoro-D-glucose in tumor imaging with positron emission tomography. Mol Imaging Biology. 2002;4:267–273
  60. DeGrado TR, Coleman RE, Wang S, et al. Synthesis and evaluation of 18F-labeled choline as an oncologic tracer for positron emission tomography: Initial findings in prostate cancer. Cancer Res. 2001;61:110–117
  61. Yoshimoto M, Waki A, Yonekura Y, et al. Characterization of acetate metabolism in tumor cells in relation to cell proliferation: Acetate metabolism in tumor cells. Nucl Med Biol. 2001;28:117–122
  62. Kurhanewicz J, Swanson MG, Nelson SJ, Vigneron DB. Combined magnetic resonance imaging and spectroscopic imaging approach to molecular imaging of prostate cancer. J Magn Reson Imaging. 2002;16:451–463
  63. Husarik DB, Miralbell R, Dubs M, et al. Evaluation of [(18)F]-choline PET/CT for staging and restaging of prostate cancer. Eur J Nucl Med Mol Imaging. 2008;(in press)
  64. de Jong IJ, Pruim J, Elsinga PH, Vaalburg W, Mensink HJ. Preoperative staging of pelvic lymph nodes in prostate cancer by (11)C-choline PET. J Nucl Med. 2003;44:331–335
  65. Cimitan M, Bortolus R, Morassut S, et al. [(18)F]fluorocholine PET/CT imaging for the detection of recurrent prostate cancer at PSA relapse: Experience in 100 consecutive patients. Eur J Nucl Med Mol Imaging. 2006;33:1387–1398
  66. Scattoni V, Picchio M, Suardi N, et al. Detection of lymph-node metastases with integrated [11C]choline PET/CT in patients with PSA failure after radical retropubic prostatectomy: Results confirmed by open pelvic-retroperitoneal lymphadenectomy. Eur Urol. 2007;52:423–429
  67. Picchio M, Messa C, Landoni C, et al. Value of [11C]choline-positron emission tomography for re-staging prostate cancer: A comparison with [18F]fluorodeoxyglucose-positron emission tomography. J Urol. 2003;169:1337–1340
  68. Reske S, Blumstein N, Glatting G. [(11)C]choline PET/CT imaging in occult local relapse of prostate cancer after radical prostatectomy. Eur J Nucl Med Mol Imaging. 2008;35:9–17
  69. de Jong IJ, Pruim J, Elsinga PH, et al. Visualisation of bladder cancer using (11)C-choline PET: first clinical experience. Eur J Nucl Med Mol Imaging. 2002;29:1283–1288
  70. Picchio M, Treiber U, Beer AJ, et al. Value of 11C-choline PET and contrast-enhanced CT for staging of bladder cancer: correlation with histopathologic findings. J Nucl Med. 2006;47:938–944
  71. Talbot JN, Gutman F, Fartoux L, et al. PET/CT in patients with hepatocellular carcinoma using [(18)F]fluorocholine: Preliminary comparison with [(18)F]FDG PET/CT. Eur J Nucl Med Mol Imaging. 2006;33:1285–1289
  72. Kwee SA, Ko JP, Jiang CS, et al. Solitary brain lesions enhancing at MR imaging: Evaluation with fluorine 18 fluorocholine PET. Radiology. 2007;244:557–565
  73. Ramirez de Molina A, Sarmentero-Estrada J, Belda-Iniesta C, et al. Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: A retrospective study. Lancet Oncol. 2007;8:889–897
  74. Mankoff DA, Dehdashti F, Shields AF. Characterizing tumors using metabolic imaging: PET imaging of cellular proliferation and steroid receptors. Neoplasia. 2000;2:71–88
  75. Shields AF, Grierson JR, Dohmen BM, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med. 1998;4:1334–1336
  76. Rasey JS, Grierson JR, Wiens LW, et al. Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med. 2002;43:1210–1217
  77. Schwartz JL, Tamura Y, Jordan R, et al. Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs. J Nucl Med. 2003;44:2027–2032
  78. Barthel H, Cleij MC, Collingridge DR, et al. 3′-deoxy-3′-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res. 2003;63:3791–3798
  79. Waldherr C, Mellinghoff IK, Tran C, et al. Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3′-deoxy-3′-18F-fluorothymidine PET. J Nucl Med. 2005;46:114–120
  80. Vesselle H, Grierson J, Muzi M, et al. In vivo validation of 3′deoxy-3′-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: Correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res. 2002;8:3315–3323
  81. Buck AK, Halter G, Schirrmeister H, et al. Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG. J Nucl Med. 2003;44:1426–1431
  82. Pio BS, Park CK, Pietras R, et al. Usefulness of 3′-[F-18]fluoro-3′-deoxythymidine with positron emission tomography in predicting breast cancer response to therapy. Mol Imaging Biol. 2006;8:36–42
  83. Buck AK, Bommer M, Stilgenbauer S, et al. Molecular imaging of proliferation in malignant lymphoma. Cancer Res. 2006;66:11055–11061
  84. Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med. 2005;46:945–952
  85. Cobben DC, van der Laan BF, Maas B, et al. 18F-FLT PET for visualization of laryngeal cancer: Comparison with 18F-FDG PET. J Nucl Med. 2004;45:226–231
  86. van Westreenen HL, Cobben DC, Jager PL, et al. Comparison of 18F-FLT PET and 18F-FDG PET in esophageal cancer. J Nucl Med. 2005;46:400–404
  87. Francis DL, Visvikis D, Costa DC, et al. Potential impact of [18F]3′-deoxy-3′-fluorothymidine versus [18F]fluoro-2-deoxy-D-glucose in positron emission tomography for colorectal cancer. Eur J Nucl Med Mol Imaging. 2003;30:988–994
  88. Wagner M, Seitz U, Buck A, et al. 3′-[18F]fluoro-3′-deoxythymidine ([18F]-FLT) as positron emission tomography tracer for imaging proliferation in a murine B-Cell lymphoma model and in the human disease. Cancer Res. 2003;63:2681–2687
  89. Yap CS, Czernin J, Fishbein MC, et al. Evaluation of thoracic tumors with 18F-fluorothymidine and 18F-fluorodeoxyglucose-positron emission tomography. Chest. 2006;129:393–401
  90. Apisarnthanarax S, Alauddin MM, Mourtada F, et al. Early detection of chemoradioresponse in esophageal carcinoma by 3′-deoxy-3′-3H-fluorothymidine using preclinical tumor models. Clin Cancer Res. 2006;12:4590–4597
  91. Herrmann K, Wieder HA, Buck AK, et al. Early response assessment using 3′-deoxy-3′-[18F]fluorothymidine-positron emission tomography in high-grade non-Hodgkin’s lymphoma. Clin Cancer Res. 2007;13:3552–3558
  92. Chen W, Delaloye S, Silverman DH, et al. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol. 2007;25:4714–4721
  93. Kenny L, Coombes RC, Vigushin DM, et al. Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3′-deoxy-3′-[(18)F]fluorothymidine positron emission tomography. Eur J Nucl Med Mol Imaging. 2007;34:1339–1347
  94. Wieder HA, Geinitz H, Rosenberg R, et al. PET imaging with [18F]3′-deoxy-3′-fluorothymidine for prediction of response to neoadjuvant treatment in patients with rectal cancer. Eur J Nucl Med Mol Imaging. 2007;34:878–883
  95. Molthoff CF, Klabbers BM, Berkhof J, et al. Monitoring Response to Radiotherapy in Human Squamous Cell Cancer Bearing Nude Mice: Comparison of 2′-deoxy-2′-[(18)F]fluoro-D: -glucose (FDG) and 3′-[(18)F]fluoro-3′-deoxythymidine (FLT). Mol Imaging Biol. 2007;9:340–347
  96. Perumal M, Pillai RG, Barthel H, et al. Redistribution of nucleoside transporters to the cell membrane provides a novel approach for imaging thymidylate synthase inhibition by positron emission tomography. Cancer Res. 2006;66:8558–8564
  97. Sun H, Mangner TJ, Collins JM, et al. Imaging DNA synthesis in vivo with 18F-FMAU and PET. J Nucl Med. 2005;46:292–296
  98. Bading JR, Shahinian AH, Bathija P, et al. Pharmacokinetics of the thymidine analog 2′-fluoro-5-[(14)C]-methyl-1-beta-D-arabinofuranosyluracil ([(14)C]FMAU) in rat prostate tumor cells. Nucl Med Biol. 2000;27:361–368
  99. Tehrani OS, Muzik O, Heilbrun LK, et al. Tumor imaging using 1-(2′-deoxy-2′-18F-fluoro-beta-D-Arabinofuranosyl)Thymine and PET. J Nucl Med. 2007;48:1436–1441
  100. Hockel M, Schlenger K, Aral B, et al. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56:4509–4515
  101. Stadler P, Becker A, Feldmann HJ, et al. Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 1999;44:749–754
  102. Teicher BA. Hypoxia and drug resistance. Cancer Metastasis Rev. 1994;13:139–168
  103. Brizel DM, Sibley GS, Prosnitz LR, et al. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997;38:285–289
  104. Eschmann SM, Paulsen F, Reimold M, et al. Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy. J Nucl Med. 2005;46:253–260
  105. Nordsmark M, Bentzen SM, Rudat V, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy (An international multi-center study). Radiother Oncol. 2005;77:18–24
  106. Barendsen GW, Koot CJ, Van Kersen GR, et al. The effect of oxygen on impairment of the proliferative capacity of human cells in culture by ionizing radiations of different LET. Int J Radiat Biol Relat Stud Phys Chem Med. 1966;10:317–327
  107. Hockel M, Schlenger K, Mitze M, et al. Hypoxia and radiation response in human tumors. Semin Radiat Oncol. 1996;6:3–9
  108. Gabalski EC, Adam M, Pinto H, et al. Pretreatment and midtreatment measurement of oxygen tension levels in head and neck cancers. Laryngoscope. 1998;108:1856–1860
  109. Tatum JL, Kelloff GJ, Gillies RJ, 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;82:699–757
  110. Geng L, Donnelly E, McMahon G, et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res. 2001;61:2413–2419
  111. Harada H, Kizaka-Kondoh S, Li G, et al. Significance of HIF-1-active cells in angiogenesis and radioresistance. Oncogene. 2007;26:7508–7516
  112. Franovic A, Gunaratnam L, Smith K, et al. Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc Natl Acad Sci USA. 2007;104:13092–13097
  113. Rasey JS, Koh WJ, Evans ML, et al. Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: A pretherapy study of 37 patients. Int J Radiat Oncol Biol Phys. 1996;36:417–428
  114. Urtasun RC, Parliament MB, McEwan AJ, et al. Measurement of hypoxia in human tumours by non-invasive SPECT imaging of iodoazomycin arabinoside. Br J Cancer Suppl. 1996;27:S209–S212
  115. Koch CJ, Hahn SM, Rockwell K, et al. Pharmacokinetics of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] in human patients: implications for hypoxia measurements in vivo by 2-nitroimidazoles. Cancer Chemother Pharmacol. 2001;48:177–187
  116. Dehdashti F, Grigsby PW, Mintun MA, et al. Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report. Int J Radiat Oncol Biol Phys. 2003;55:1233–1238
  117. Lehtio K, Oikonen V, Gronroos T, et al. Imaging of blood flow and hypoxia in head and neck cancer: initial evaluation with [(15)O]H(2)O and [(18)F]fluoroerythronitroimidazole PET. J Nucl Med. 2001;42:1643–1652
  118. Piert M, Machulla HJ, Picchio M, et al. Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside. J Nucl Med. 2005;46:106–113
  119. Rajendran JG, Mankoff DA, O’Sullivan F, et al. Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. Clin Cancer Res. 2004;10:2245–2252
  120. Chaudary N, Hill RP. Hypoxia and metastasis. Clin Cancer Res. 2007;13:1947–1949
  121. Lanzen J, Braun RD, Klitzman B, et al. Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor. Cancer Res. 2006;66:2219–2223
  122. Smallbone K, Gavaghan DJ, Maini PK, et al. Quiescence as a mechanism for cyclical hypoxia and acidosis. J Math Biol. 2007;55:767–779
  123. Jain RK. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science. 2005;307:58–62
  124. Brurberg KG, Skogmo HK, Graff BA, et al. Fluctuations in pO2 in poorly and well-oxygenated spontaneous canine tumors before and during fractionated radiation therapy. Radiother Oncol. 2005;77:220–226
  125. Ljungkvist AS, Bussink J, Kaanders JH, et al. Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers. Radiat Res. 2007;167:127–145
  126. Thorwarth D, Eschmann SM, Scheiderbauer J, et al. Kinetic analysis of dynamic 18F-fluoromisonidazole PET correlates with radiation treatment outcome in head-and-neck cancer. BMC Cancer. 2005;5:152
  127. Zanzonico P, O’Donoghue J, Chapman JD, et al. Iodine-124-labeled iodo-azomycin-galactoside imaging of tumor hypoxia in mice with serial microPET scanning. Eur J Nucl Med Mol imaging. 2004;31:117–128
  128. Mahy P, De Bast M, Leveque PH, et al. Preclinical validation of the hypoxia tracer 2-(2-nitroimidazol-1-yl)-N-(3,3,3-[(18)F]trifluoropropyl)acetamide, [(18)F]EF3. Eur J Nucl Med Mol Imaging. 2004;31:1263–1272
  129. Ziemer LS, Evans SM, Kachur AV, et al. Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5. Eur J Nucl Med Mol Imaging. 2003;30:259–266
  130. Lewis JS, McCarthy DW, McCarthy TJ, Fujibayashi Y, Welch MJ. Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model. J Nucl Med. 1999;40:177–183
  131. Lewis JS, Sharp TL, Laforest R, Fujibayashi Y, Welch MJ. Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): Effect of changes in tissue oxygenation. J Nucl Med. 2001;42:655–661
  132. O’Donoghue JA, Zanzonico P, Pugachev A, et al. Assessment of regional tumor hypoxia using 18F-fluoromisonidazole and 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) positron emission tomography: Comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models. Int J Radiat Oncol Biol Phys. 2005;61:1493–1502
  133. Burgman P, O’Donoghue JA, Lewis JS, et al. Cell line-dependent differences in uptake and retention of the hypoxia-selective nuclear imaging agent Cu-ATSM. Nucl Med Biol. 2005;32:623–630
  134. Rosenberg A, Knox S. Radiation sensitization with redox modulators: A promising approach. Int J Radiat Oncol Biol Phys. 2006;64:343–354
  135. Kaanders JH, Pop LA, Marres HA, et al. ARCON: Experience in 215 patients with advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2002;52:769–778
  136. 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;24:2098–2104
  137. Rischin D, Fisher R, Peters L, et al. Hypoxia in head and neck cancer: Studies with hypoxic positron emission tomography imaging and hypoxic cytotoxins. Int J Radiat Oncol Biol Phys. 2007;69:S61–S63
  138. Chao KS, Bosch WR, Mutic S, et al. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2001;49:1171–1182
  139. Grosu AL, Souvatzoglou M, Roper B, et al. Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 2007;69:541–551
  140. Lee NY, Mechalakos JG, Nehmeh S, et al. Fluorine-18-labeled fluoromisonidazole positron emission and computed tomography-guided intensity-modulated radiotherapy for head and neck cancer: A feasibility study. Int J Radiat Oncol Biol Phys. 2007;
  141. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10:145–147
  142. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342
  143. Beer AJ, Grosu AL, Carlsen J, et al. [18F]Galacto-RGD positron emission tomography for imaging of {alpha}v{beta}3 expression on the neovasculature in patients with squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13:6610–6616
  144. Beer AJ, Haubner R, Goebel M, et al. Biodistribution and pharmacokinetics of the alphavbeta3-selective tracer 18F-galacto-RGD in cancer patients. J Nucl Med. 2005;46:1333–1341
  145. Haubner R, Weber WA, Beer AJ, et al. Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD. PLoS Med. 2005;2:e70
  146. Clezardin P. Recent insights into the role of integrins in cancer metastasis. Cell Mol Life Sci. 1998;54:541–548
  147. Hockel M, Vaupel P. Tumor hypoxia: Definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93:266–276
  148. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47
  149. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: Role of the HIF system. Nat Med. 2003;9:677–684
  150. Li XF, Carlin S, Urano M, et al. Visualization of hypoxia in microscopic tumors by immunofluorescent microscopy. Cancer Res. 2007;67:7646–7653
  151. Grierson JR, Yagle KJ, Eary JF, et al. Production of [F-18]fluoroannexin for imaging apoptosis with PET. Bioconjug Chem. 2004;15:373–379
  152. Taki J, Higuchi T, Kawashima A, et al. Effect of postconditioning on myocardial 99mTc-annexin-V uptake: Comparison with ischemic preconditioning and caspase inhibitor treatment. J Nucl Med. 2007;48:1301–1307
  153. Keen HG, Dekker BA, Disley L, et al. Imaging apoptosis in vivo using 124I-annexin V and PET. Nucl Med Biol. 2005;32:395–402
  154. Cauchon N, Langlois R, Rousseau JA, et al. PET imaging of apoptosis with (64)Cu-labeled streptavidin following pretargeting of phosphatidylserine with biotinylated annexin-V. Eur J Nucl Med Mol Imaging. 2007;34:247–258

PII: S0001-2998(07)00144-4

doi: 10.1053/j.semnuclmed.2007.11.006

Seminars in Nuclear Medicine
Volume 38, Issue 2 , Pages 119-128 , March 2008

Article Tools