Seminars in Nuclear Medicine
Volume 31, Issue 4 , Pages 312-320 , October 2001

Monitoring gene therapy with reporter gene imaging

  • Pritha Ray

      Affiliations

    • Crupm Institute for Molecular Imaging, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Biomathematics, UCLA School of Medicine, Los Angeles, CA USA
    • Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA USA
    • UCLA-Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA USA
  • ,
  • Eileen Bauer

      Affiliations

    • Crupm Institute for Molecular Imaging, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Biomathematics, UCLA School of Medicine, Los Angeles, CA USA
    • Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA USA
    • UCLA-Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA USA
  • ,
  • Meera Lyer

      Affiliations

    • Crupm Institute for Molecular Imaging, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Biomathematics, UCLA School of Medicine, Los Angeles, CA USA
    • Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA USA
    • UCLA-Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA USA
  • ,
  • Jorge R. Barrio

      Affiliations

    • Crupm Institute for Molecular Imaging, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Biomathematics, UCLA School of Medicine, Los Angeles, CA USA
    • Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA USA
    • UCLA-Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA USA
  • ,
  • Nagichettiar Satyamurthy

      Affiliations

    • Crupm Institute for Molecular Imaging, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Biomathematics, UCLA School of Medicine, Los Angeles, CA USA
    • Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA USA
    • UCLA-Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA USA
  • ,
  • Michael E. Phelps

      Affiliations

    • Crupm Institute for Molecular Imaging, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Biomathematics, UCLA School of Medicine, Los Angeles, CA USA
    • Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA USA
    • UCLA-Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA USA
  • ,
  • Harvey R. Herschman

      Affiliations

    • Crupm Institute for Molecular Imaging, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Biomathematics, UCLA School of Medicine, Los Angeles, CA USA
    • Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA USA
    • UCLA-Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA USA
  • ,
  • Sanjiv Sam Gambhir

      Affiliations

    • Crupm Institute for Molecular Imaging, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA USA
    • Department of Biomathematics, UCLA School of Medicine, Los Angeles, CA USA
    • Molecular Biology Institute, UCLA School of Medicine, Los Angeles, CA USA
    • UCLA-Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, CA USA
    • Corresponding Author InformationAddress reprint requests to Sanjiv Sam Gambhir, MD, PhD, Crump Institute for Molecular Imaging, UCLA School of Medicine, B3-399A BRI, Box 951770, Los Angeles, CA 90095-1770.

References 

  1. Hall SJ, Chen SH, Woo SLC. The promise and reality of cancer gene therapy. Am J Human Genet. 1997;61:785–789
  2. Gomez-Navarro J, Curiel DT, Douglas JT. Gene therapy for cancer. Eur J Cancer. 1999;35:867–885
  3. Cooper JM. Non-infectious gene transfer and expression systems for cancer gene therapy. In: Lattime E, Gerson S editor. Gene Therapy of Cancer. San Diego, CA: Academic Press; 1999;p. 77–89
  4. Grandaliano G, Choudhury GG, Abboud HE. Transgenic animal models as a tool in the diagnosis of kidney diseases. Sem Neph. 1995;15:43–49
  5. Ikenaka K, Kagawa T. Transgenic systems in study-ing myelin gene expression. Develop Neurosci. 1995;17:127–136
  6. Misslitz A, Mottram JC, Overath P, et al. Targeted integration into a rRNA locus results in uniform and high level expression of transgenes in leishmania amastigotes. Mol Biochem Parasitol. 2000;107:251–261
  7. discussion 32–3 Lee JH, Federoff HJ, Schoeniger LO. G207, modified herpes simplex virus type 1, kills human pancreatic cancer cells in vitro. J Gastro Surg. 1999;3:127–131
  8. Zhou D, Zhou C, Chen S. Gene regulation studies of aromatase expression in breast cancer and adipose stromal cells. J Steroid Biochem Mol Biol. 1997;61:273–280
  9. [in Japanese] Nomura T, Takakura Y, Hashida M. Cancer gene therapy by direct intratumoral injection: Gene expression and intratumoral pharmacokinetics of plasmid DNA. Gan To Kagaku Ryoho. 1997;24:483–488
  10. Gnant MF, Noll LA, Irvine KR, et al. Tumor-specific gene delivery using recombinant vaccinia virus in a rabbit model of liver metastases. J Natl Cancer Inst. 1999;91:1744–1750
  11. Karp M, Oker-Blom C. A streptavidin-luciferase fusion protein: Comparisons and applications. Biomol Eng. 1999;16:101–104
  12. Kunert A, Hagemann M, Erdmann N. Construction of promoter probe vectors for Synechocystis sp. PCC 6803 using the light-emitting reporter systems Gfp and LuxAB. J Microbiol Methods. 2000;41:185–194
  13. Seul KH, Beyer EC. Mouse connexin37: Gene structure and promoter analysis. Biochim Biophys Acta. 2000;1492:499–504
  14. Leffel SM, Mabon SA, Stewart CN. Applications of green fluorescent protein in plants. Biotechniques. 1997;23:912–918
  15. Sauvonnet N, Pugsley AP. Identification of two regions of Klebsiella oxytoca pullulanase that together are capable of promoting betalactamase secretion by the general secretory pathway. Mol Microbiol. 1996;22:1–7
  16. Contag CH, Jenkins D, Contag PR, et al. Use of reporter genes for optical measurements of neoplastic disease in vivo. Neoplasia. 2000;2:41–52
  17. Cherry SR, Shao Y, Silverman RW, et al. MicroPET: A highresolution PET scanner for imaging small animals. IEEE Trans Nucl Sci. 1997;44:1161–1166
  18. Phelps ME. PET: A biological imaging technique. Neurochem Res. 1991;16:929–994
  19. Gambhir SS, Herschman HR, Cherry SR, et al. Imaging transgene expression with radionuclide imaging technologies. Neoplasia. 2000;2:118–138
  20. Haberkorn U, Oberdorfer F, Gebert J, et al. Monitoring of gene therapy with cytosine deaminase: In vitro studies using 3H-5-fluorocytosine. J Nucl Med. 1996;37:87–94
  21. Stegman LD, Rehemtulla A, Beattie B, et al. Noninvasive quantitation of cytosine deaminase transgene expression in human tumor xenografts with in vivo magnetic resonance spectroscopy. Proc Natl Acad Sci USA. 1999;96:9821–9826
  22. Gambhir SS, Barrio JR, Herschman HR, et al. Imaging gene expression: Principles and assays. J Nucl Cardiol. 1999;6:219–233
  23. Gambhir SS, Bauer E, Black ME, et al. A mutant herpes simplex virus type 1 thymidine kinase reporter gene shows improved sensitivity for imaging reporter gene expression with positron emission tomography. Proc Natl Acad Sci USA. 2000;97:2785–2790
  24. MacLaren DC, Gambhir SS, Cherry SR, et al. Repetitive and non-invasive in vivo imaging of reporter gene expression using andenovirus-delivered dopamine D2 receptor as a PET reporter gene and FESP as a PET reporter probe. J Nucl Med. 1998;39:35P
  25. MacLaren DC, Gambhir SS, Satyamurthy N, et al. Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals. Gene Therapy. 1999;6:785–791
  26. Q Liang, N Satyamurthy, JR Barrio, et al: Noninvasive, quantitative imaging, in living animals, of a mutant dopamine D2 receptor reporter gene in which ligand binding is uncoupled from signal transduction. Gene Therapy (in press)
  27. Iyer M, Barrio JR, Namavari M, et al. 8-[F-18]fluoropenciclovir: An improved reporter probe for imaging HSV1-tk reporter gene expression in vivo using PET. J Nucl Med. 2001;42:96–105
  28. Rogers BE, Zinn KR, Buchsbaum DJ. Gene transfer strategies for improving radiolabeled peptide imaging and therapy. Q J Nucl Med. 2000;44:208–223
  29. Loimas S, Wahlfors J, Jänne J. Herpes simplex virus thymidine kinase-green fluorescent protein fusion gene: New tool for gene transfer studies and gene therapy. Biotechniques. 1998;24:614–618
  30. Steffens S, Frank S, Fischer U, et al. Enhanced green fluorescent protein fusion proteins of herpes simplex virus type 1 thymidine kinase and cytochrome P450 4B1: Applications for prodrug-activating gene therapy. Cancer Gene Ther. 2000;7:806–812
  31. Jacobs A, Dubrovin M, Hewett J, et al. Functional coexpression of HSV-1 thymidine kinase and green fluorescent protein: Implications for noninvasive imaging of transgene expression. Neoplasia. 1999;1:154–161
  32. Strathdee CA, McLeod MR, Underhill TM. Dominant positive and negative selection using luciferase, green fluorescent protein and betagalactosidase reporter gene fusions. Biotechniques. 2000;28:210–212
  33. Sonenberg N, Pelletier J. Poliovirus translation—a paradigm for a novel initiation mechanism. Bioessays. 1989;11:128–132
  34. Jang SK, Kräusslich HG, Nicklin MJ, et al. A segment of the 5′ nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J Virol. 1988;62:2636–2643
  35. Jang SK, Davies MV, Kaufman RJ, et al. Initiation of protein synthesis by internal entry of ribosomes into the 5′ nontranslated region of encephalomyocarditis virus RNA in vivo. J Virol. 1989;63:1651–1660
  36. Yu Y, Annala AJ, Barrio JR, et al. Quantification of target gene expression by imaging reporter gene expression in living animals. Nat Med. 2000;6:933–937
  37. Tjuvajev JG, Joshi A, Callegari J, et al. A general approach to the non-invasive imaging of transgenes using cis-linked herpes simplex virus thymidine kinase. Neoplasia. 1999;1:315–320
  38. Kamoshita N, Tsukiyama-Kohara K, Kohara M, et al. Genetic analysis of internal ribosomal entry site on hepatitis C virus RNA: Implication for involvement of the highly ordered structure and cell type-specific transacting factors. Virol. 1997;233:9–18
  39. Yaghoubi SS, Wu L, Liang Q, et al. Direct correlation between positron emission tomographic images of two reporter genes delivered by two distinct adenoviral vectors. Gene Therapy. 2001;1072–1080
  40. Sun X, Annala A, Yaghoubi S, et al: Quantitative imaging of gene induction in living animals. Gene Therapy (in press)
  41. Louie AY, Huber MM, Ahrens ET. In vivo visualization of gene expression using magnetic resonance imaging. Nat Biotech. 2000;18:321–325
  42. Weissleder R, Moore A, Mahmood U, et al. In vivo magnetic resonance imaging of transgene expression. Nat Med. 2000;6:351–355
  43. Bogdanov A, Weissleder R. The development of in vivo imaging systems to study gene expression. Trends Biotechnol. 1998;16:5–10
  44. Contag PR, Olomu IN, Stevenson DK, et al. Bioluminescent indicators in living mammals. Nat Med. 1998;4:245–247
  45. Yang M, Baranov E, Jiang P, et al. Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. Proc Natl Acad Sci U S A. 2000;97:1206–1211
  46. Yaghoubi SS, Barrio JR, Dahlbom M, et al: Human pharmacokinetics and dosiometry studies of [18F]FHBG: A reporter probe for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene expression. J Nucl Med (in press)
  47. Jacobs A, Braunlich I, Graf R, et al. Quantitative kinetics of [I-124]FIAU in cat and man. J Nucl Med. 2001;42:467–475
  48. Herschman HR, MacLaren DC, Iyer M, et al. Seeing is believing: Non-invasive, quantitative and repetitive imaging of reporter gene expression in living animals, using positron emission tomography. J Neurosci Res. 2000;59:699–705
  49. Green L, Nyugen K, Bauer E, et al. Indirect monitoring of endogenous gene expression by imaging PET reporter gene in transgenic mice. J Nucl Med. 2000;41:81P
  50. Tjuvajev JG, Finn R, Watanabe K, et al. Noninvasive imaging of herpes virus thymidine kinase gene transfer and expression: A potential method for monitoring clinical gene therapy. Cancer Res. 1996;56:4087–4095
  51. Tjuvajev JG, Chen SH, Joshi A, et al. Imaging adenoviral-mediated herpes virus thymidine kinase gene transfer expression in vivo. Cancer Res. 1999;59:5186–5193
  52. Tjuvajev JG, Avril N, Oku T, et al. Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography. Cancer Res. 1998;58:4333–4341
  53. Haubner R, Avril N, Hantzopoulos PA, et al. In vivo imaging of herpes simplex virus type 1 thymidine kinas gene expression: early kinetics of radiolabelled FIAU. E J Nucl Med. 2000;27:283–291
  54. Morin KW, Atrazheva ED, Knaus EE, et al. Synthesis and cellular uptake of 2′-substituted analogues of (E)-5-(2-[125I]Iodovinyl-2′-deoxyuridine in tumor cells transduced with the herpes simplex type-1 thymidine kinase gene. Evaluation as probes for monitoring gene therapy. J Med Chem. 1997;40:2184–2190
  55. Wiebe LI, Knaus EE, Morin KW. Radiolabelled pyrimidine nucleosides to monitor the expression of HSV-1 thymidine kinase in gene therapy. Nucleosides Nucleotides. 1999;18:1065–1066
  56. Germann C, Shields AF, Grierson JR, et al. 5-Fluoro-1-(2′-deoxy-2′-fluoro-beta-D-ribofuranosyl) uracil trapping in Morris hepatoma cells expressing the herpes simplex virus thymidine kinase gene. J Nucl Med. 1998;39:1418–1423
  57. Haberkorn U, Altmann A, Morr I, et al. Monitoring gene therapy with herpes simplex virus thymidine kinase in hepatoma cells: Uptake of specific substrates. J Nucl med. 1997;38:287–294
  58. Haberkorn U, Khazaie K, Morr I, et al. Ganciclovir uptake in human mammary carcinoma cells expressing herpes simplex virus thymidine kinase. Nucl Med Biol. 1998;25:367–373
  59. Gambhir SS, Barrio J, Wu L, et al. Imaging of adenoviral-directed herpes simplex virus type 1 thymidine kinase gene expression in mice with ganciclovir. J Nucl Med. 1998;39:2003–2011
  60. Gambhir SS, Barrio JR, Phelps ME, et al. Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography. Proc Natl Acad Sci U S A. 1999;96:2333–2338
  61. Alauddin MM, Conti PS, Mazza SM, et al. 9-[(3-[18F]-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]-FHPG): A potential imaging agent of viral infection and gene therapy using PET. Nucl Med Biol. 1996;23:787–792
  62. Alauddin MM, Shahinian A, Kundu RK, et al. Evaluation of 9-[(3-18F-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]-FHPG) in vitro and in vivo as a probe for PET imaging of gene incorporation and expression in tumors. Nucl Med Biol. 1999;26:371–376
  63. de Vries EFJ, van Waarde A, Harmsen MC, et al. [C-11]FMAU and [F-18]FHPG as PET tracers for herpes simplex virus thymidine kinase enzyme activity and human cytomegalovirus infections. Nucl Med Biol. 2000;27:113–119
  64. Hospers GAP, Calogero A, van Waarde A, et al. Monitoring of herpes simplex virus thymidine kinase enzyme activity using positron emission tomography. Cancer Res. 2000;60:1488–1491
  65. Hustinx R, Shiue CY, Alavi A, et al. Imaging in vivo herpes simplex virus thymidine kinase gene transfer to tumour-bearing rodents using positron emission tomography and [F-18]FHPG. E J Nucl Med. 2001;28:5–12
  66. Alauddin MM, Conti PS. Synthesis and preliminary evaluation of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG): A new potential imaging agent for viral infection and gene therapy using PET. Nucl Med Biol. 1998;25:175–180
  67. Rogers BE, McLean SF, Kirkman RL, et al. In vivo localization of [(111)In-DTPA-D-Phe1-octreotide to human ovarian tumor xenografts induced to express the somatostatin receptor subtype 2 using an adenoviral vector. Clin Cancer Res. 1999;5:383–393
  68. Buchsbaum DJ, Rogers BE, Khazaeli MB, et al. Targeting strategies for cancer radiotherapy. Clin Cancer Res. 1999;5:3048s–3055s
  69. Zinn KR, Buchsbaum DJ, Chaudhuri TR, et al. Noninvasive monitoring of gene transfer using a reporter receptor imaged with a high-affinity peptide radiolabeled with Tc-99m or Re-188. J Nucl Med. 2000;41:887–895
  70. Bogdanov AJ, Simonova M, Weissleder R. Design of metal-binding green fluorescent protein variants. Biochim Biophys Acta. 1998;1397:56–64
  71. Bogdanov A, Petherick P, Marecos E, et al. In vivo localization of diglycylcysteine-bearing synthetic peptides by nuclear imaging of oxotechnetate transchelation. Nucl Med Biol. 1997;24:739–742
  72. Rogers BE, Rosenfeld ME, Khazaeli MB, et al. Localization of iodine-125-mIP-Des-Met14-bombesin (7–13)NH2 in ovarian carcinoma induced to express the gastrin-releasing peptide receptor by adenoviral vector-mediated gene transfer. J Nucl Med. 1997;38:1221–1229
  73. Rogers BE, Curiel DT, Mayo MS, et al. Tumor localization of a radiolabeled bombesin analogue in mice bearing human ovarian tumors induced to express the gastrin-releasing peptide receptor by an adenoviral vector. Cancer. 1997;80:2419–2424
  74. Rosenfeld ME, Rogers BE, Khazaeli MB, et al. Adenoviral-mediated delivery of gastrin-releasing peptide receptor results in specific tumor localization of a bombesin analogue in vivo. Clin Cancer Res. 1997;3:1187–1194
  75. Baidoo KE, Scheffel U, Stathis M, et al. High-affinity no-carrieradded 99mTc-labeled chemotactic peptides for studies of inflammation in vivo. Bioconjugate Chem. 1998;9:208–217
  76. Haberkor U, Henza M, Altmann A, et al. Transfer of the human NaI symporter gene enhances iodide uptake in hepatoma cells. J Nucl Med. 2001;42:317–325
  77. Boland A, Ricard M, Opolon P, et al. Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy. Cancer Res. 2000;60:3484–3492
  78. Enochs WS, Petherick P, Bogdanova A, et al. Paramegnetic metal scavenging by melanin: MR imaging. Radiology. 1997;204:417–423
  79. Weissleder R, Simonova M, Bogdanova A, et al. MR imaging and scintigraphy of gene expression through melanin induction. Radiology. 1997;204:425–429
  80. Yang M, Baranov E, Li XM, et al. Whole-body and intravital optical imaging of angiogenesis in orthotopically implanted tumors. Proc Natl Acad Sci U S A. 2001;98:2616–2621
  81. Yang M, Baranov E, Moossa AR, et al. Visualizing gene expression by whole-body fluorescence imaging. Proc Natl Acad Sci U S A. 2000;97:12278–12282
  82. Yang M, Hasegawa S, Jiang P, et al. Widespread skeletal metastatic potential of human lung cancer revealed by green fluorescent protein expression. Cancer Res. 1998;58:4217–4221
  83. Yang M, Jiang P, Sun FX, et al. A fluorescent orthotopic bone metastasis model of human prostate cancer. Cancer Res. 1999;59:781–786
  84. Hasegawa S, Yang M, Chishima T, et al. In vivo tumor delivery of the green fluorescent protein gene to report future occurrence of metastasis. Cancer Gene Ther. 2000;7:1336–1340
  85. Pfeifer A, Kessler T, Yang M, et al. Transduction of liver cells by lentiviral vectors: Analysis in living animals by fluorescence imaging. Mol Ther. 2001;3:319–322
  86. Contag CH, Spilman SD, Contag PR, et al. Visualizing gene expression in living mammals using a bioluminescent reporter. Photochem Photobiol. 1997;66:523–531
  87. Tung CH, Mahmood U, Bredow S, et al. In vivo imaging of proteolytic enzyme activity using a novel molecular reporter. Cancer Res. 2000;60:4953–4958
  88. Tung CH, Bredow S, Mahmood U, et al. A cathepsin D-sensitive near-infrared fluorescence probe for in vivo imaging of enzyme activity. Bioconj Chem. 1999;10:892–896
  89. Weissleder R, Tung CH, Mahmood U, et al. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nat Biotech. 1999;17:375–378
  90. Auricchio A, Zhou R, Wilson JM, et al. In vivo detection of gene expression in liver by 31P nuclear magnetic resonance spectroscopy employing creatine kinase as a marker gene. Proc Natl Acad Sci U S A. 2001;98:5205–5210
  91. Walter G, Barton ER, Sweeney HL. Noninvasive measurement of gene expression in skeletal muscle. Proc Natl Acad Sci U S A. 2000;97:5151–5155

PII: S0001-2998(01)80010-6

doi: 10.1053/snuc.2001.26209

Seminars in Nuclear Medicine
Volume 31, Issue 4 , Pages 312-320 , October 2001