Molecular imaging in cancer treatment

Review Article

Abstract

The success of cancer therapy can be difficult to predict, as its efficacy is often predicated upon characteristics of the cancer, treatment, and individual that are not fully understood or are difficult to ascertain. Monitoring the response of disease to treatment is therefore essential and has traditionally been characterized by changes in tumor volume. However, in many instances, this singular measure is insufficient for predicting treatment effects on patient survival. Molecular imaging allows repeated in vivo measurement of many critical molecular features of neoplasm, such as metabolism, proliferation, angiogenesis, hypoxia, and apoptosis, which can be employed for monitoring therapeutic response. In this review, we examine the current methods for evaluating response to treatment and provide an overview of emerging PET molecular imaging methods that will help guide future cancer therapies.

Keywords

Molecular imaging Therapy response Metabolism Proliferation Angiogenesis Hypoxia Apoptosis 

References

  1. 1.
    Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, et al. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 2003;8:307–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009;27:2091–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005;23:2556–68.PubMedCrossRefGoogle Scholar
  4. 4.
    Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719–26.PubMedCrossRefGoogle Scholar
  5. 5.
    Heinrich S, Schäfer M, Weber A, Hany TF, Bhure U, Pestalozzi BC, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg 2008;248:1014–22.PubMedCrossRefGoogle Scholar
  6. 6.
    Rajan R, Poniecka A, Smith TL, Yang Y, Frye D, Pusztai L, et al. Change in tumor cellularity of breast carcinoma after neoadjuvant chemotherapy as a variable in the pathologic assessment of response. Cancer 2004;100:1365–73.PubMedCrossRefGoogle Scholar
  7. 7.
    Vecchio FM, Valentini V, Minsky BD, Padula GD, Venkatraman ES, Balducci M, et al. The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer. Int J Radiat Oncol Biol Phys 2005;62:752–60.PubMedCrossRefGoogle Scholar
  8. 8.
    Goffin J, Baral S, Tu D, Nomikos D, Seymour L. Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval. Clin Cancer Res 2005;11:5928–34.PubMedCrossRefGoogle Scholar
  9. 9.
    Ratain MJ, Eckhardt SG. Phase II studies of modern drugs directed against new targets: if you are fazed, too, then resist RECIST. J Clin Oncol 2004;22:4442–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32.PubMedCrossRefGoogle Scholar
  11. 11.
    Ford R, Schwartz L, Dancey J, Dodd LE, Eisenhauer EA, Gwyther S, et al. Lessons learned from independent central review. Eur J Cancer 2009;45:268–74.PubMedCrossRefGoogle Scholar
  12. 12.
    Usami N, Iwano S, Yokoi K. Solitary fibrous tumor of the pleura: evaluation of the origin with 3D CT angiography. J Thorac Oncol 2007;2:1124–5.PubMedCrossRefGoogle Scholar
  13. 13.
    McDonald DM, Choyke PL. Imaging of angiogenesis: from microscope to clinic. Nat Med 2003;9:713–25.PubMedCrossRefGoogle Scholar
  14. 14.
    van Vliet M, van Dijke CF, Wielopolski PA, ten Hagen TL, Veenland JF, Preda A, et al. MR angiography of tumor-related vasculature: from the clinic to the micro-environment. Radiographics 2005;25 Suppl 1:S85–97. discussion S97–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Boudghene FP, Gouny P, Tassart M, Callard P, Le Breton C, Vayssairat M. Subungual glomus tumor: combined use of MRI and three-dimensional contrast MR angiography. J Magn Reson Imaging 1998;8:1326–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Foote RL, Weidner N, Harris J, Hammond E, Lewis JE, Vuong T, et al. Evaluation of tumor angiogenesis measured with microvessel density (MVD) as a prognostic indicator in nasopharyngeal carcinoma: results of RTOG 9505. Int J Radiat Oncol Biol Phys 2005;61:745–53.PubMedCrossRefGoogle Scholar
  17. 17.
    El-Assal ON, Yamanoi A, Soda Y, Yamaguchi M, Igarashi M, Yamamoto A, et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology 1998;27:1554–62.PubMedCrossRefGoogle Scholar
  18. 18.
    Giatromanolaki A, Koukourakis M, O’Byrne K, Fox S, Whitehouse R, Talbot DC, et al. Prognostic value of angiogenesis in operable non-small cell lung cancer. J Pathol 1996;179:80–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Miles KA. Tumour angiogenesis and its relation to contrast enhancement on computed tomography: a review. Eur J Radiol 1999;30:198–205.PubMedCrossRefGoogle Scholar
  20. 20.
    O’Connor JP, Jayson GC, Jackson A, Ghiorghiu D, Carrington BM, Rose CJ, et al. Enhancing fraction predicts clinical outcome following first-line chemotherapy in patients with epithelial ovarian carcinoma. Clin Cancer Res 2007;13:6130–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Braga L, Semelka RC, Pietrobon R, Martin D, de Barros N, Guller U. Does hypervascularity of liver metastases as detected on MRI predict disease progression in breast cancer patients? AJR Am J Roentgenol 2004;182:1207–13.PubMedGoogle Scholar
  22. 22.
    Chow KL, Gobin YP, Cloughesy T, Sayre JW, Villablanca JP, Viñuela F. Prognostic factors in recurrent glioblastoma multiforme and anaplastic astrocytoma treated with selective intra-arterial chemotherapy. AJNR Am J Neuroradiol 2000;21:471–8.PubMedGoogle Scholar
  23. 23.
    Hawighorst H, Knapstein PG, Knopp MV, Weikel W, Brix G, Zuna I, et al. Uterine cervical carcinoma: comparison of standard and pharmacokinetic analysis of time-intensity curves for assessment of tumor angiogenesis and patient survival. Cancer Res 1998;58:3598–602.PubMedGoogle Scholar
  24. 24.
    Mayr NA, Yuh WT, Magnotta VA, Ehrhardt JC, Wheeler JA, Sorosky JI, et al. Tumor perfusion studies using fast magnetic resonance imaging technique in advanced cervical cancer: a new noninvasive predictive assay. Int J Radiat Oncol Biol Phys 1996;36:623–33.PubMedCrossRefGoogle Scholar
  25. 25.
    Evelhoch JL. Key factors in the acquisition of contrast kinetic data for oncology. J Magn Reson Imaging 1999;10:254–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Choyke PL, Dwyer AJ, Knopp MV. Functional tumor imaging with dynamic contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging 2003;17:509–20.PubMedCrossRefGoogle Scholar
  27. 27.
    O’Connor JP, Jackson A, Parker GJ, Jayson GC. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br J Cancer 2007;96:189–95.PubMedCrossRefGoogle Scholar
  28. 28.
    Zee YK, O’Connor JP, Parker GJ, Jackson A, Clamp AR, Taylor MB, et al. Imaging angiogenesis of genitourinary tumors. Nat Rev Urol 2010;7:69–82.PubMedCrossRefGoogle Scholar
  29. 29.
    Miles KA, Charnsangavej C, Lee FT, Fishman EK, Horton K, Lee TY. Application of CT in the investigation of angiogenesis in oncology. Acad Radiol 2000;7:840–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Hahn OM, Yang C, Medved M, Karczmar G, Kistner E, Karrison T, et al. Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. J Clin Oncol 2008;26:4572–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Marzola P, Degrassi A, Calderan L, Farace P, Crescimanno C, Nicolato E, et al. In vivo assessment of antiangiogenic activity of SU6668 in an experimental colon carcinoma model. Clin Cancer Res 2004;10:739–50.PubMedCrossRefGoogle Scholar
  32. 32.
    Kim S, Loevner LA, Quon H, Kilger A, Sherman E, Weinstein G, et al. Prediction of response to chemoradiation therapy in squamous cell carcinomas of the head and neck using dynamic contrast-enhanced MR imaging. AJNR Am J Neuroradiol 2010;31:262–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Jensen LR, Huuse EM, Bathen TF, Goa PE, Bofin AM, Pedersen TB, et al. Assessment of early docetaxel response in an experimental model of human breast cancer using DCE-MRI, ex vivo HR MAS, and in vivo 1H MRS. NMR Biomed 2010;23:56–65.PubMedCrossRefGoogle Scholar
  34. 34.
    Morgan B, Thomas AL, Drevs J, Hennig J, Buchert M, Jivan A, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 2003;21:3955–64.PubMedCrossRefGoogle Scholar
  35. 35.
    Medved M, Karczmar G, Yang C, Dignam J, Gajewski TF, Kindler H, et al. Semiquantitative analysis of dynamic contrast enhanced MRI in cancer patients: variability and changes in tumor tissue over time. J Magn Reson Imaging 2004;20:122–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Liu G, Rugo HS, Wilding G, McShane TM, Evelhoch JL, Ng C, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol 2005;23:5464–73.PubMedCrossRefGoogle Scholar
  37. 37.
    Paldino MJ, Barboriak DP. Fundamentals of quantitative dynamic contrast-enhanced MR imaging. Magn Reson Imaging Clin N Am 2009;17:277–89.PubMedCrossRefGoogle Scholar
  38. 38.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.PubMedCrossRefGoogle Scholar
  39. 39.
    Chen X. Multimodality imaging of tumor integrin alphavbeta3 expression. Mini Rev Med Chem 2006;6:227–34.PubMedCrossRefGoogle Scholar
  40. 40.
    Cai W, Chen X. Multimodality imaging of vascular endothelial growth factor and vascular endothelial growth factor receptor expression. Front Biosci 2007;12:4267–79.PubMedCrossRefGoogle Scholar
  41. 41.
    Cai W, Chen X. Multimodality molecular imaging of tumor angiogenesis. J Nucl Med 2008;49 Suppl 2:113S–28.PubMedCrossRefGoogle Scholar
  42. 42.
    Cai W, Sam Gambhir S, Chen X. Multimodality tumor imaging targeting integrin alphavbeta3. Biotechniques 2005;39:S14–25.PubMedCrossRefGoogle Scholar
  43. 43.
    Hillner BE, Siegel BA, Liu D, Shields AF, Gareen IF, Hanna L, et al. Impact of positron emission tomography/computed tomography and positron emission tomography (PET) alone on expected management of patients with cancer: initial results from the National Oncologic PET Registry. J Clin Oncol 2008;26:2155–61.PubMedCrossRefGoogle Scholar
  44. 44.
    Wahl RL, Zasadny K, Helvie M, Hutchins GD, Weber B, Cody R. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation. J Clin Oncol 1993;11:2101–11.PubMedGoogle Scholar
  45. 45.
    Larson SM, Schwartz LH. 18F-FDG PET as a candidate for “qualified biomarker”: functional assessment of treatment response in oncology. J Nucl Med 2006;47:901–3.PubMedGoogle Scholar
  46. 46.
    Weber WA, Wieder H. Monitoring chemotherapy and radiotherapy of solid tumors. Eur J Nucl Med Mol Imaging 2006;33 Suppl 1:27–37.PubMedCrossRefGoogle Scholar
  47. 47.
    Weber WA. Assessing tumor response to therapy. J Nucl Med 2009;50 Suppl 1:1S–0.PubMedCrossRefGoogle Scholar
  48. 48.
    de Geus-Oei LF, Vriens D, van Laarhoven HW, van der Graaf WT, Oyen WJ. Monitoring and predicting response to therapy with 18F-FDG PET in colorectal cancer: a systematic review. J Nucl Med 2009;50 Suppl 1:43S–54.PubMedCrossRefGoogle Scholar
  49. 49.
    Brundage MD, Davies D, Mackillop WJ. Prognostic factors in non-small cell lung cancer: a decade of progress. Chest 2002;122:1037–57.PubMedCrossRefGoogle Scholar
  50. 50.
    Hicks RJ. Role of 18F-FDG PET in assessment of response in non-small cell lung cancer. J Nucl Med 2009;50 Suppl 1:31S–42.PubMedCrossRefGoogle Scholar
  51. 51.
    Mac Manus MP, Hicks RJ, Matthews JP, McKenzie A, Rischin D, Salminen EK, 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;21:1285–92.PubMedCrossRefGoogle Scholar
  52. 52.
    Avril N, Sassen S, Roylance R. Response to therapy in breast cancer. J Nucl Med 2009;50 Suppl 1:55S–63.PubMedCrossRefGoogle Scholar
  53. 53.
    McDermott GM, Welch A, Staff RT, Gilbert FJ, Schweiger L, Semple SI, et al. Monitoring primary breast cancer throughout chemotherapy using FDG-PET. Breast Cancer Res Treat 2007;102:75–84.PubMedCrossRefGoogle Scholar
  54. 54.
    Krause BJ, Herrmann K, Wieder H, zum Büschenfelde CM. 18F-FDG PET and 18F-FDG PET/CT for assessing response to therapy in esophageal cancer. J Nucl Med 2009;50 Suppl 1:89S–96.PubMedCrossRefGoogle Scholar
  55. 55.
    Klaeser B, Nitzsche E, Schuller JC, Köberle D, Widmer L, Balmer-Majno S, et al. Limited predictive value of FDG-PET for response assessment in the preoperative treatment of esophageal cancer: results of a prospective multi-center trial (SAKK 75/02). Onkologie 2009;32:724–30.PubMedCrossRefGoogle Scholar
  56. 56.
    Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–86.PubMedCrossRefGoogle Scholar
  57. 57.
    Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 2009;50 Suppl 1:122S–50.PubMedCrossRefGoogle Scholar
  58. 58.
    Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 1999;35:1773–82.PubMedCrossRefGoogle Scholar
  59. 59.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47.PubMedCrossRefGoogle Scholar
  60. 60.
    Chen W, Silverman DH, Delaloye S, Czernin J, Kamdar N, Pope W, et al. 18F-FDOPA PET imaging of brain tumors: comparison study with 18F-FDG PET and evaluation of diagnostic accuracy. J Nucl Med 2006;47:904–11.PubMedGoogle Scholar
  61. 61.
    Cheng YM, Ho CL, Chiu NT, Hsu KF. Cesarean section scar mimicking uterine malignant neoplasm at positron emission tomography/computed tomography. J Minim Invasive Gynecol 2009;16:372–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Christman D, Crawford EJ, Friedkin M, Wolf AP. Detection of DNA synthesis in intact organisms with positron-emitting (methyl-11C)thymidine. Proc Natl Acad Sci U S A 1972;69:988–92.PubMedCrossRefGoogle Scholar
  63. 63.
    Rubini JR, Cronkite EP, Bond VP, Fliedner TM. The metabolism and fate of tritiated thymidine in man. J Clin Invest 1960;39:909–18.PubMedCrossRefGoogle Scholar
  64. 64.
    Bading JR, Shields AF. Imaging of cell proliferation: status and prospects. J Nucl Med 2008;49 Suppl 2:64S–80.PubMedCrossRefGoogle Scholar
  65. 65.
    Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 1998;4:1334–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Been LB, Suurmeijer AJ, Cobben DC, Jager PL, Hoekstra HJ, Elsinga PH. [18F]FLT-PET in oncology: current status and opportunities. Eur J Nucl Med Mol Imaging 2004;31:1659–72.PubMedCrossRefGoogle Scholar
  67. 67.
    Yap CS, Czernin J, Fishbein MC, Cameron RB, Schiepers C, Phelps ME, et al. Evaluation of thoracic tumors with 18F-fluorothymidine and 18F-fluorodeoxyglucose-positron emission tomography. Chest 2006;129:393–401.PubMedCrossRefGoogle Scholar
  68. 68.
    Buck AK, Schirrmeister H, Hetzel M, Von Der Heide M, Halter G, Glatting G, et al. 3-deoxy-3-[(18)F]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules. Cancer Res 2002;62:3331–4.PubMedGoogle Scholar
  69. 69.
    Chen W, Cloughesy T, Kamdar N, Satyamurthy N, Bergsneider M, Liau L, et al. Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med 2005;46:945–52.PubMedGoogle Scholar
  70. 70.
    Kenny LM, Vigushin DM, Al-Nahhas A, Osman S, Luthra SK, Shousha S, et al. Quantification of cellular proliferation in tumor and normal tissues of patients with breast cancer by [18F]fluorothymidine-positron emission tomography imaging: evaluation of analytical methods. Cancer Res 2005;65:10104–12.PubMedCrossRefGoogle Scholar
  71. 71.
    van Westreenen HL, Cobben DC, Jager PL, van Dullemen HM, Wesseling J, Elsinga PH, et al. Comparison of 18F-FLT PET and 18F-FDG PET in esophageal cancer. J Nucl Med 2005;46:400–4.PubMedGoogle Scholar
  72. 72.
    de Langen AJ, Klabbers B, Lubberink M, Boellaard R, Spreeuwenberg MD, Slotman BJ, et al. Reproducibility of quantitative 18F-3′-deoxy-3′-fluorothymidine measurements using positron emission tomography. Eur J Nucl Med Mol Imaging 2009;36:389–95.PubMedCrossRefGoogle Scholar
  73. 73.
    Yang YJ, Ryu JS, Kim SY, Oh SJ, Im KC, Lee H, et al. Use of 3′-deoxy-3′-[18F]fluorothymidine PET to monitor early responses to radiation therapy in murine SCCVII tumors. Eur J Nucl Med Mol Imaging 2006;33:412–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Sugiyama M, Sakahara H, Sato K, Harada N, Fukumoto D, Kakiuchi T, et al. Evaluation of 3′-deoxy-3′-18F-fluorothymidine for monitoring tumor response to radiotherapy and photodynamic therapy in mice. J Nucl Med 2004;45:1754–8.PubMedGoogle Scholar
  75. 75.
    Molthoff CF, Klabbers BM, Berkhof J, Felten JT, van Gelder M, Windhorst AD, et al. Monitoring response to radiotherapy in human squamous cell cancer bearing nude mice: comparison of 2′-deoxy-2′-[18F]fluoro-D-glucose (FDG) and 3′-[18F]fluoro-3′-deoxythymidine (FLT). Mol Imaging Biol 2007;9:340–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Buck AK, Kratochwil C, Glatting G, Juweid M, Bommer M, Tepsic D, et al. Early assessment of therapy response in malignant lymphoma with the thymidine analogue [18F]FLT. Eur J Nucl Med Mol Imaging 2007;34:1775–82.PubMedCrossRefGoogle Scholar
  77. 77.
    Pan MH, Huang SC, Liao YP, Schaue D, Wang CC, Stout DB, et al. FLT-PET imaging of radiation responses in murine tumors. Mol Imaging Biol 2008;10:325–34.PubMedCrossRefGoogle Scholar
  78. 78.
    Buck AK, Halter G, Schirrmeister H, Kotzerke J, Wurziger I, Glatting G, et al. Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG. J Nucl Med 2003;44:1426–31.PubMedGoogle Scholar
  79. 79.
    Choi SJ, Kim JS, Kim JH, Oh SJ, Lee JG, Kim CJ, et al. [18F]3′-deoxy-3′-fluorothymidine PET for the diagnosis and grading of brain tumors. Eur J Nucl Med Mol Imaging 2005;32:653–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Kenny L, Coombes RC, Vigushin DM, Al-Nahhas A, Shousha S, Aboagye EO. Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography. Eur J Nucl Med Mol Imaging 2007;34:1339–47.PubMedCrossRefGoogle Scholar
  81. 81.
    Sohn HJ, Yang YJ, Ryu JS, Oh SJ, Im KC, Moon DH, et al. [18F]Fluorothymidine positron emission tomography before and 7 days after gefitinib treatment predicts response in patients with advanced adenocarcinoma of the lung. Clin Cancer Res 2008;14:7423–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Muzi M, Vesselle H, Grierson JR, Mankoff DA, Schmidt RA, Peterson L, et al. Kinetic analysis of 3′-deoxy-3′-fluorothymidine PET studies: validation studies in patients with lung cancer. J Nucl Med 2005;46:274–82.PubMedGoogle Scholar
  83. 83.
    Troost EG, Vogel WV, Merkx MA, Slootweg PJ, Marres HA, Peeters WJ, et al. 18F-FLT PET does not discriminate between reactive and metastatic lymph nodes in primary head and neck cancer patients. J Nucl Med 2007;48:726–35.PubMedCrossRefGoogle Scholar
  84. 84.
    Schwartz JL, Tamura Y, Jordan R, Grierson JR, Krohn KA. Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs. J Nucl Med 2003;44:2027–32.PubMedGoogle Scholar
  85. 85.
    Reske SN, Deisenhofer S. Is 3′-deoxy-3′-(18)F-fluorothymidine a better marker for tumour response than (18)F-fluorodeoxyglucose? Eur J Nucl Med Mol Imaging 2006;33 Suppl 1:38–43.PubMedCrossRefGoogle Scholar
  86. 86.
    Leenders WP, Küsters B, de Waal RM. Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis. Endothelium 2002;9:83–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature 2000;407:242–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Auguste P, Lemiere S, Larrieu-Lahargue F, Bikfalvi A. Molecular mechanisms of tumor vascularization. Crit Rev Oncol Hematol 2005;54:53–61.PubMedCrossRefGoogle Scholar
  90. 90.
    Herbst RS, Mullani NA, Davis DW, Hess KR, McConkey DJ, Charnsangavej C, et al. Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin. J Clin Oncol 2002;20:3804–14.PubMedCrossRefGoogle Scholar
  91. 91.
    Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer 2002;2:91–100.PubMedCrossRefGoogle Scholar
  92. 92.
    Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 1994;264:569–71.PubMedCrossRefGoogle Scholar
  93. 93.
    Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002;110:673–87.PubMedCrossRefGoogle Scholar
  94. 94.
    Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins. Science 1987;238:491–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Pepper MS. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol 2001;21:1104–17.PubMedCrossRefGoogle Scholar
  96. 96.
    Hynes RO, Bader BL, Hodivala-Dilke K. Integrins in vascular development. Braz J Med Biol Res 1999;32:501–10.PubMedCrossRefGoogle Scholar
  97. 97.
    Cai W, Chen X. Anti-angiogenic cancer therapy based on integrin alphavbeta3 antagonism. Anticancer Agents Med Chem 2006;6:407–28.PubMedCrossRefGoogle Scholar
  98. 98.
    Mizejewski GJ. Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med 1999;222:124–38.PubMedCrossRefGoogle Scholar
  99. 99.
    Haubner R, Wester HJ, Reuning U, Senekowitsch-Schmidtke R, Diefenbach B, Kessler H, et al. Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting. J Nucl Med 1999;40:1061–71.PubMedGoogle Scholar
  100. 100.
    Chen X, Park R, Shahinian AH, Bading JR, Conti PS. Pharmacokinetics and tumor retention of 125I-labeled RGD peptide are improved by PEGylation. Nucl Med Biol 2004;31:11–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Haubner R. Alphavbeta3-integrin imaging: a new approach to characterise angiogenesis? Eur J Nucl Med Mol Imaging 2006;33 Suppl 1:54–63.PubMedCrossRefGoogle Scholar
  102. 102.
    Gurrath M, Müller G, Kessler H, Aumailley M, Timpl R. Conformation/activity studies of rationally designed potent anti-adhesive RGD peptides. Eur J Biochem 1992;210:911–21.PubMedCrossRefGoogle Scholar
  103. 103.
    van Hagen PM, Breeman WA, Bernard HF, Schaar M, Mooij CM, Srinivasan A, et al. Evaluation of a radiolabelled cyclic DTPA-RGD analogue for tumour imaging and radionuclide therapy. Int J Cancer 2000;90:186–98.PubMedCrossRefGoogle Scholar
  104. 104.
    Chen X, Hou Y, Tohme M, Park R, Khankaldyyan V, Gonzales-Gomez I, et al. Pegylated Arg-Gly-Asp peptide: 64Cu labeling and PET imaging of brain tumor alphavbeta3-integrin expression. J Nucl Med 2004;45:1776–83.PubMedGoogle Scholar
  105. 105.
    Li ZB, Chen K, Chen X. (68)Ga-labeled multimeric RGD peptides for microPET imaging of integrin alpha(v)beta (3) expression. Eur J Nucl Med Mol Imaging 2008;35:1100–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Noiri E, Goligorsky MS, Wang GJ, Wang J, Cabahug CJ, Sharma S, et al. Biodistribution and clearance of 99mTc-labeled Arg-Gly-Asp (RGD) peptide in rats with ischemic acute renal failure. J Am Soc Nephrol 1996;7:2682–8.PubMedGoogle Scholar
  107. 107.
    Beer AJ, Haubner R, Goebel M, Luderschmidt S, Spilker ME, Wester HJ, et al. Biodistribution and pharmacokinetics of the alphavbeta3-selective tracer 18F-galacto-RGD in cancer patients. J Nucl Med 2005;46:1333–41.PubMedGoogle Scholar
  108. 108.
    Beer AJ, Haubner R, Wolf I, Goebel M, Luderschmidt S, Niemeyer M, et al. PET-based human dosimetry of 18F-galacto-RGD, a new radiotracer for imaging alpha v beta3 expression. J Nucl Med 2006;47:763–9.PubMedGoogle Scholar
  109. 109.
    Beer AJ, Haubner R, Sarbia M, Goebel M, Luderschmidt S, Grosu AL, et al. Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man. Clin Cancer Res 2006;12:3942–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Beer AJ, Lorenzen S, Metz S, Herrmann K, Watzlowik P, Wester HJ, et al. Comparison of integrin alphaVbeta3 expression and glucose metabolism in primary and metastatic lesions in cancer patients: a PET study using 18F-galacto-RGD and 18F-FDG. J Nucl Med 2008;49:22–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Liu S, Hsieh WY, Jiang Y, Kim YS, Sreerama SG, Chen X, et al. Evaluation of a (99m)Tc-labeled cyclic RGD tetramer for noninvasive imaging integrin alpha(v)beta3-positive breast cancer. Bioconjug Chem 2007;18:438–46.PubMedCrossRefGoogle Scholar
  112. 112.
    Li ZB, Cai W, Cao Q, Chen K, Wu Z, He L, et al. (64)Cu-labeled tetrameric and octameric RGD peptides for small-animal PET of tumor alpha(v)beta(3) integrin expression. J Nucl Med 2007;48:1162–71.PubMedCrossRefGoogle Scholar
  113. 113.
    Liu Z, Liu S, Wang F, Chen X. Noninvasive imaging of tumor integrin expression using (18)F-labeled RGD dimer peptide with PEG(4) linkers. Eur J Nucl Med Mol Imaging 2009;36:1296–307.PubMedCrossRefGoogle Scholar
  114. 114.
    Kim S, Bell K, Mousa SA, Varner JA. Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol 2000;156:1345–62.PubMedGoogle Scholar
  115. 115.
    Renner W, Pilger E. Simultaneous in vivo quantitation of vascular endothelial growth factor mRNA splice variants. J Vasc Res 1999;36:133–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 1992;267:26031–7.PubMedGoogle Scholar
  117. 117.
    Ferrara N. The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS 2005;94:209–31.PubMedGoogle Scholar
  118. 118.
    Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 2006;312:549–60.PubMedCrossRefGoogle Scholar
  119. 119.
    Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581–611.PubMedCrossRefGoogle Scholar
  120. 120.
    Nagengast WB, de Vries EG, Hospers GA, Mulder NH, de Jong JR, Hollema H, et al. In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. J Nucl Med 2007;48:1313–9.PubMedCrossRefGoogle Scholar
  121. 121.
    Jayson GC, Zweit J, Jackson A, Mulatero C, Julyan P, Ranson M, et al. Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies. J Natl Cancer Inst 2002;94:1484–93.PubMedGoogle Scholar
  122. 122.
    Scheer MG, Stollman TH, Boerman OC, Verrijp K, Sweep FC, Leenders WP, et al. Imaging liver metastases of colorectal cancer patients with radiolabelled bevacizumab: lack of correlation with VEGF-A expression. Eur J Cancer 2008;44:1835–40.PubMedCrossRefGoogle Scholar
  123. 123.
    Cai W, Chen K, Mohamedali KA, Cao Q, Gambhir SS, Rosenblum MG, et al. PET of vascular endothelial growth factor receptor expression. J Nucl Med 2006;47:2048–56.PubMedGoogle Scholar
  124. 124.
    Chen K, Cai W, Li ZB, Wang H, Chen X. Quantitative PET imaging of VEGF receptor expression. Mol Imaging Biol 2009;11:15–22.PubMedCrossRefGoogle Scholar
  125. 125.
    Hsu AR, Cai W, Veeravagu A, Mohamedali KA, Chen K, Kim S, et al. Multimodality molecular imaging of glioblastoma growth inhibition with vasculature-targeting fusion toxin VEGF121/rGel. J Nucl Med 2007;48:445–54.PubMedGoogle Scholar
  126. 126.
    George SJ. Therapeutic potential of matrix metalloproteinase inhibitors in atherosclerosis. Expert Opin Investig Drugs 2000;9:993–1007.PubMedCrossRefGoogle Scholar
  127. 127.
    Folgueras AR, Pendás AM, Sánchez LM, López-Otin C. Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol 2004;48:411–24.PubMedCrossRefGoogle Scholar
  128. 128.
    Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002;90:251–62.PubMedGoogle Scholar
  129. 129.
    Pellikainen JM, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ, Kosma VM. Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis. Clin Cancer Res 2004;10:7621–8.PubMedCrossRefGoogle Scholar
  130. 130.
    Juuti A, Lundin J, Nordling S, Louhimo J, Haglund C. Epithelial MMP-2 expression correlates with worse prognosis in pancreatic cancer. Oncology 2006;71:61–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Lee LY, Wu CM, Wang CC, Yu JS, Liang Y, Huang KH, et al. Expression of matrix metalloproteinases MMP-2 and MMP-9 in gastric cancer and their relation to claudin-4 expression. Histol Histopathol 2008;23:515–21.PubMedGoogle Scholar
  132. 132.
    Koivunen E, Arap W, Valtanen H, Rainisalo A, Medina OP, Heikkilä P, et al. Tumor targeting with a selective gelatinase inhibitor. Nat Biotechnol 1999;17:768–74.PubMedCrossRefGoogle Scholar
  133. 133.
    Hanaoka H, Mukai T, Habashita S, Asano D, Ogawa K, Kuroda Y, et al. Chemical design of a radiolabeled gelatinase inhibitor peptide for the imaging of gelatinase activity in tumors. Nucl Med Biol 2007;34:503–10.PubMedCrossRefGoogle Scholar
  134. 134.
    Sprague JE, Li WP, Liang K, Achilefu S, Anderson CJ. In vitro and in vivo investigation of matrix metalloproteinase expression in metastatic tumor models. Nucl Med Biol 2006;33:227–37.PubMedCrossRefGoogle Scholar
  135. 135.
    MacPherson LJ, Bayburt EK, Capparelli MP, Carroll BJ, Goldstein R, Justice MR, et al. Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. J Med Chem 1997;40:2525–32.PubMedCrossRefGoogle Scholar
  136. 136.
    Scozzafava A, Supuran CT. Carbonic anhydrase and matrix metalloproteinase inhibitors: sulfonylated amino acid hydroxamates with MMP inhibitory properties act as efficient inhibitors of CA isozymes I, II, and IV, and N-hydroxysulfonamides inhibit both these zinc enzymes. J Med Chem 2000;43:3677–87.PubMedCrossRefGoogle Scholar
  137. 137.
    Zheng QH, Fei X, Liu X, Wang JQ, Bin Sun H, Mock BH, et al. Synthesis and preliminary biological evaluation of MMP inhibitor radiotracers [11C]methyl-halo-CGS 27023A analogs, new potential PET breast cancer imaging agents. Nucl Med Biol 2002;29:761–70.PubMedCrossRefGoogle Scholar
  138. 138.
    Zheng QH, Fei X, DeGrado TR, Wang JQ, Stone KL, Martinez TD, et al. Synthesis, biodistribution and micro-PET imaging of a potential cancer biomarker carbon-11 labeled MMP inhibitor (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [11C]methyl ester. Nucl Med Biol 2003;30:753–60.PubMedCrossRefGoogle Scholar
  139. 139.
    Neri D, Carnemolla B, Nissim A, Leprini A, Querzè G, Balza E, et al. Targeting by affinity-matured recombinant antibody fragments of an angiogenesis associated fibronectin isoform. Nat Biotechnol 1997;15:1271–5.PubMedCrossRefGoogle Scholar
  140. 140.
    Pini A, Viti F, Santucci A, Carnemolla B, Zardi L, Neri P, et al. Design and use of a phage display library. Human antibodies with subnanomolar affinity against a marker of angiogenesis eluted from a two-dimensional gel. J Biol Chem 1998;273:21769–76.PubMedCrossRefGoogle Scholar
  141. 141.
    Santimaria M, Moscatelli G, Viale GL, Giovannoni L, Neri G, Viti F, et al. Immunoscintigraphic detection of the ED-B domain of fibronectin, a marker of angiogenesis, in patients with cancer. Clin Cancer Res 2003;9:571–9.PubMedGoogle Scholar
  142. 142.
    Carnemolla B, Castellani P, Ponassi M, Borsi L, Urbini S, Nicolo G, et al. Identification of a glioblastoma-associated tenascin-C isoform by a high affinity recombinant antibody. Am J Pathol 1999;154:1345–52.PubMedGoogle Scholar
  143. 143.
    Silacci M, Brack SS, Späth N, Buck A, Hillinger S, Arni S, et al. Human monoclonal antibodies to domain C of tenascin-C selectively target solid tumors in vivo. Protein Eng Des Sel 2006;19:471–8.PubMedCrossRefGoogle Scholar
  144. 144.
    Marron MB, Singh H, Tahir TA, Kavumkal J, Kim HZ, Koh GY, et al. Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. J Biol Chem 2007;282:30509–17.PubMedCrossRefGoogle Scholar
  145. 145.
    Seaman S, Stevens J, Yang MY, Logsdon D, Graff-Cherry C, St Croix B. Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 2007;11:539–54.PubMedCrossRefGoogle Scholar
  146. 146.
    Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 1996;56:941–3.PubMedGoogle Scholar
  147. 147.
    Höckel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, et al. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 1993;26:45–50.PubMedCrossRefGoogle Scholar
  148. 148.
    Souvatzoglou M, Grosu AL, Röper B, Krause BJ, Beck R, Reischl G, et al. Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study. Eur J Nucl Med Mol Imaging 2007;34:1566–75.PubMedCrossRefGoogle Scholar
  149. 149.
    Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 2007;26:225–39.PubMedCrossRefGoogle Scholar
  150. 150.
    Ljungkvist AS, Bussink J, Kaanders JH, van der Kogel AJ. Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers. Radiat Res 2007;167:127–45.PubMedCrossRefGoogle Scholar
  151. 151.
    Lucignani G. PET imaging with hypoxia tracers: a must in radiation therapy. Eur J Nucl Med Mol Imaging 2008;35:838–42.PubMedCrossRefGoogle Scholar
  152. 152.
    Gallez B, Baudelet C, Jordan BF. Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications. NMR Biomed 2004;17:240–62.PubMedCrossRefGoogle Scholar
  153. 153.
    Dunn JF, O’Hara JA, Zaim-Wadghiri Y, Lei H, Meyerand ME, Grinberg OY, et al. Changes in oxygenation of intracranial tumors with carbogen: a BOLD MRI and EPR oximetry study. J Magn Reson Imaging 2002;16:511–21.PubMedCrossRefGoogle Scholar
  154. 154.
    Padhani A. PET imaging of tumour hypoxia. Cancer Imaging 2006;6:S117–21.PubMedCrossRefGoogle Scholar
  155. 155.
    Nehmeh SA, Lee NY, Schröder H, Squire O, Zanzonico PB, Erdi YE, et al. Reproducibility of intratumor distribution of (18)F-fluoromisonidazole in head and neck cancer. Int J Radiat Oncol Biol Phys 2008;70:235–42.PubMedCrossRefGoogle Scholar
  156. 156.
    Rajendran JG, Schwartz DL, O’Sullivan J, Peterson LM, Ng P, Scharnhorst J, et al. Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin Cancer Res 2006;12:5435–41.PubMedCrossRefGoogle Scholar
  157. 157.
    Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, 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.PubMedCrossRefGoogle Scholar
  158. 158.
    Spence AM, Muzi M, Swanson KR, O’Sullivan F, Rockhill JK, Rajendran JG, et al. Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival. Clin Cancer Res 2008;14:2623–30.PubMedCrossRefGoogle Scholar
  159. 159.
    Eschmann SM, Paulsen F, Reimold M, Dittmann H, Welz S, Reischl G, 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;46:253–60.PubMedGoogle Scholar
  160. 160.
    Rajendran JG, Hendrickson KR, Spence AM, Muzi M, Krohn KA, Mankoff DA. Hypoxia imaging-directed radiation treatment planning. Eur J Nucl Med Mol Imaging 2006;33 Suppl 1:44–53.PubMedCrossRefGoogle Scholar
  161. 161.
    Reischl G, Dorow DS, Cullinane C, Katsifis A, Roselt P, Binns D, et al. Imaging of tumor hypoxia with [124I]IAZA in comparison with [18F]FMISO and [18F]FAZA—first small animal PET results. J Pharm Pharm Sci 2007;10:203–11.PubMedGoogle Scholar
  162. 162.
    Evans SM, Fraker D, Hahn SM, Gleason K, Jenkins WT, Jenkins K, et al. EF5 binding and clinical outcome in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys 2006;64:922–7.PubMedCrossRefGoogle Scholar
  163. 163.
    Evans SM, Judy KD, Dunphy I, Jenkins WT, Nelson PT, Collins R, et al. Comparative measurements of hypoxia in human brain tumors using needle electrodes and EF5 binding. Cancer Res 2004;64:1886–92.PubMedCrossRefGoogle Scholar
  164. 164.
    Minn H, Grönroos TJ, Komar G, Eskola O, Lehtiö K, Tuomela J, et al. Imaging of tumor hypoxia to predict treatment sensitivity. Curr Pharm Des 2008;14:2932–42.PubMedCrossRefGoogle Scholar
  165. 165.
    Kaneta T, Takai Y, Iwata R, Hakamatsuka T, Yasuda H, Nakayama K, et al. Initial evaluation of dynamic human imaging using 18F-FRP170 as a new PET tracer for imaging hypoxia. Ann Nucl Med 2007;21:101–7.PubMedCrossRefGoogle Scholar
  166. 166.
    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;40:177–83.PubMedGoogle Scholar
  167. 167.
    Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H, Konishi J, Yokoyama A. Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med 1997;38:1155–60.PubMedGoogle Scholar
  168. 168.
    Lewis JS, Herrero P, Sharp TL, Engelbach JA, Fujibayashi Y, Laforest R, et al. Delineation of hypoxia in canine myocardium using PET and copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone). J Nucl Med 2002;43:1557–69.PubMedGoogle Scholar
  169. 169.
    Takahashi N, Fujibayashi Y, Yonekura Y, Welch MJ, Waki A, Tsuchida T, et al. Copper-62 ATSM as a hypoxic tissue tracer in myocardial ischemia. Ann Nucl Med 2001;15:293–6.PubMedCrossRefGoogle Scholar
  170. 170.
    Takahashi N, Fujibayashi Y, Yonekura Y, Welch MJ, Waki A, Tsuchida T, et al. Evaluation of 62Cu labeled diacetyl-bis(N4-methylthiosemicarbazone) as a hypoxic tissue tracer in patients with lung cancer. Ann Nucl Med 2000;14:323–8.PubMedCrossRefGoogle Scholar
  171. 171.
    Dietz DW, Dehdashti F, Grigsby PW, Malyapa RS, Myerson RJ, Picus J, et al. Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study. Dis Colon Rectum 2008;51:1641–8.PubMedCrossRefGoogle Scholar
  172. 172.
    Dehdashti F, Grigsby PW, Mintun MA, Lewis JS, Siegel BA, Welch MJ. 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;55:1233–8.PubMedCrossRefGoogle Scholar
  173. 173.
    Lewis JS, Laforest R, Dehdashti F, Grigsby PW, Welch MJ, Siegel BA. An imaging comparison of 64Cu-ATSM and 60Cu-ATSM in cancer of the uterine cervix. J Nucl Med 2008;49:1177–82.PubMedCrossRefGoogle Scholar
  174. 174.
    Lohith TG, Kudo T, Demura Y, Umeda Y, Kiyono Y, Fujibayashi Y, et al. Pathophysiologic correlation between 62Cu-ATSM and 18F-FDG in lung cancer. J Nucl Med 2009;50:1948–53.PubMedCrossRefGoogle Scholar
  175. 175.
    Yuan H, Schroeder T, Bowsher JE, Hedlund LW, Wong T, Dewhirst MW. Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone). J Nucl Med 2006;47:989–98.PubMedGoogle Scholar
  176. 176.
    Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239–57.PubMedCrossRefGoogle Scholar
  177. 177.
    Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 1992;148:2207–16.PubMedGoogle Scholar
  178. 178.
    Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995;267:1456–62.PubMedCrossRefGoogle Scholar
  179. 179.
    Hersey P, Zhang XD, Mhaidat N. Overcoming resistance to apoptosis in cancer therapy. Adv Exp Med Biol 2008;615:105–26.PubMedCrossRefGoogle Scholar
  180. 180.
    Emoto K, Toyama-Sorimachi N, Karasuyama H, Inoue K, Umeda M. Exposure of phosphatidylethanolamine on the surface of apoptotic cells. Exp Cell Res 1997;232:430–4.PubMedCrossRefGoogle Scholar
  181. 181.
    Zwaal RF, Comfurius P, Bevers EM. Surface exposure of phosphatidylserine in pathological cells. Cell Mol Life Sci 2005;62:971–88.PubMedCrossRefGoogle Scholar
  182. 182.
    Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, et al. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med 1995;182:1545–56.PubMedCrossRefGoogle Scholar
  183. 183.
    van Engeland M, Kuijpers HJ, Ramaekers FC, Reutelingsperger CP, Schutte B. Plasma membrane alterations and cytoskeletal changes in apoptosis. Exp Cell Res 1997;235:421–30.PubMedCrossRefGoogle Scholar
  184. 184.
    Blankenberg FG, Katsikis PD, Tait JF, Davis RE, Naumovski L, Ohtsuki K, et al. Imaging of apoptosis (programmed cell death) with 99mTc annexin V. J Nucl Med 1999;40:184–91.PubMedGoogle Scholar
  185. 185.
    Blankenberg FG, Katsikis PD, Tait JF, Davis RE, Naumovski L, Ohtsuki K, et al. In vivo detection and imaging of phosphatidylserine expression during programmed cell death. Proc Natl Acad Sci U S A 1998;95:6349–54.PubMedCrossRefGoogle Scholar
  186. 186.
    Belhocine T, Steinmetz N, Hustinx R, Bartsch P, Jerusalem G, Seidel L, et al. Increased uptake of the apoptosis-imaging agent (99m)Tc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clin Cancer Res 2002;8:2766–74.PubMedGoogle Scholar
  187. 187.
    Boersma HH, Liem IH, Kemerink GJ, Thimister PW, Hofstra L, Stolk LM, et al. Comparison between human pharmacokinetics and imaging properties of two conjugation methods for 99mTc-annexin A5. Br J Radiol 2003;76:553–60.PubMedCrossRefGoogle Scholar
  188. 188.
    Kemerink GJ, Liu X, Kieffer D, Ceyssens S, Mortelmans L, Verbruggen AM, et al. Safety, biodistribution, and dosimetry of 99mTc-HYNIC-annexin V, a novel human recombinant annexin V for human application. J Nucl Med 2003;44:947–52.PubMedGoogle Scholar
  189. 189.
    Van den Brande JM, Koehler TC, Zelinkova Z, Bennink RJ, te Velde AA, ten Cate FJ, et al. Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn’s disease. Gut 2007;56:509–17.PubMedCrossRefGoogle Scholar
  190. 190.
    Belhocine T, Steinmetz N, Li C, Green A, Blankenberg FG. The imaging of apoptosis with the radiolabeled annexin V: optimal timing for clinical feasibility. Technol Cancer Res Treat 2004;3:23–32.PubMedGoogle Scholar
  191. 191.
    Kartachova M, van Zandwijk N, Burgers S, van Tinteren H, Verheij M, Valdés Olmos RA. Prognostic significance of 99mTc Hynic-rh-annexin V scintigraphy during platinum-based chemotherapy in advanced lung cancer. J Clin Oncol 2007;25:2534–9.PubMedCrossRefGoogle Scholar
  192. 192.
    Kartachova MS, Valdés Olmos RA, Haas RL, Hoebers FJ, van Herk M, Verheij M. 99mTc-HYNIC-rh-annexin-V scintigraphy: visual and quantitative evaluation of early treatment-induced apoptosis to predict treatment outcome. Nucl Med Commun 2008;29:39–44.PubMedCrossRefGoogle Scholar
  193. 193.
    van de Wiele C, Lahorte C, Vermeersch H, Loose D, Mervillie K, Steinmetz ND, et al. Quantitative tumor apoptosis imaging using technetium-99m-HYNIC annexin V single photon emission computed tomography. J Clin Oncol 2003;21:3483–7.PubMedCrossRefGoogle Scholar
  194. 194.
    Haas RL, de Jong D, Valdés Olmos RA, Hoefnagel CA, van den Heuvel I, Zerp SF, et al. In vivo imaging of radiation-induced apoptosis in follicular lymphoma patients. Int J Radiat Oncol Biol Phys 2004;59:782–7.PubMedCrossRefGoogle Scholar
  195. 195.
    Rottey S, Slegers G, Van Belle S, Goethals I, Van de Wiele C. Sequential 99mTc-hydrazinonicotinamide-annexin V imaging for predicting response to chemotherapy. J Nucl Med 2006;47:1813–8.PubMedGoogle Scholar
  196. 196.
    Tait JF, Smith C, Blankenberg FG. Structural requirements for in vivo detection of cell death with 99mTc-annexin V. J Nucl Med 2005;46:807–15.PubMedGoogle Scholar
  197. 197.
    Tait JF, Smith C, Levashova Z, Patel B, Blankenberg FG, Vanderheyden JL. Improved detection of cell death in vivo with annexin V radiolabeled by site-specific methods. J Nucl Med 2006;47:1546–53.PubMedGoogle Scholar
  198. 198.
    Wang F, Fang W, Zhao M, Wang Z, Ji S, Li Y, et al. Imaging paclitaxel (chemotherapy)-induced tumor apoptosis with 99mTc C2A, a domain of synaptotagmin I: a preliminary study. Nucl Med Biol 2008;35:359–64.PubMedCrossRefGoogle Scholar
  199. 199.
    Iwamoto K, Hayakawa T, Murate M, Makino A, Ito K, Fujisawa T, et al. Curvature-dependent recognition of ethanolamine phospholipids by duramycin and cinnamycin. Biophys J 2007;93:1608–19.PubMedCrossRefGoogle Scholar
  200. 200.
    Zhou D, Chu W, Rothfuss J, Zeng C, Xu J, Jones L, et al. Synthesis, radiolabeling, and in vivo evaluation of an 18F-labeled isatin analog for imaging caspase-3 activation in apoptosis. Bioorg Med Chem Lett 2006;16:5041–6.PubMedCrossRefGoogle Scholar
  201. 201.
    Haberkorn U, Kinscherf R, Krammer PH, Mier W, Eisenhut M. Investigation of a potential scintigraphic marker of apoptosis: radioiodinated Z-Val-Ala-DL-Asp(O-methyl)-fluoromethyl ketone. Nucl Med Biol 2001;28:793–8.PubMedCrossRefGoogle Scholar
  202. 202.
    Aloya R, Shirvan A, Grimberg H, Reshef A, Levin G, Kidron D, et al. Molecular imaging of cell death in vivo by a novel small molecule probe. Apoptosis 2006;11:2089–101.PubMedCrossRefGoogle Scholar
  203. 203.
    Cohen A, Ziv I, Aloya T, Levin G, Kidron D, Grimberg H, et al. Monitoring of chemotherapy-induced cell death in melanoma tumors by N,N′-Didansyl-L-cystine. Technol Cancer Res Treat 2007;6:221–34.PubMedGoogle Scholar

Copyright information

© US Government 2010

Authors and Affiliations

  1. 1.Stanford University School of MedicineStanfordUSA
  2. 2.Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB)National Institutes of Health (NIH)BethesdaUSA

Personalised recommendations