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Thymidine Kinase PET Reporter Gene Imaging of Cancer Cells In Vivo

  • Melissa N. McCracken
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1790)

Abstract

Positron emission tomography (PET) is a three dimensional imaging modality that detects the accumulation of radiolabeled isotopes in vivo. Ectopic expression of a thymidine kinase reporter gene allows for the specific detection of reporter cells in vivo by imaging with the reporter specific probe. PET reporter imaging is sensitive, quantitative and can be scaled into larger tumors or animals with little to no tissue diffraction. Here, we describe how thymidine kinase PET reporter genes can be used to noninvasively image cancer cells in vivo.

Key words

Positron emission tomography Reporter gene Noninvasive imaging Thymidine kinase [18F]-FHBG Small animal imaging Herpes Simplex Virus Thymidine Kinase HSV-TK sr39TK 

Notes

Acknowledgment

M.N.M. is supported by the Stanford Dean’s Fellowship and the A.P. Giannini Foundation.

References

  1. 1.
    Phelps ME (2000) Positron emission tomography provides molecular imaging of biological processes. Proc Natl Acad Sci U S A 97:9226–9233CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Cherry SR, Gambhir SS (2001) Use of positron emission tomography in animal research. ILAR Journal/National Research Council, Institute of Laboratory Animal Resources 42:219–232CrossRefGoogle Scholar
  3. 3.
    Gambhir SS (2002) Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2:683–693CrossRefPubMedGoogle Scholar
  4. 4.
    Kircher MF, Gambhir SS, Grimm J (2011) Noninvasive cell-tracking methods. Nat Rev Clin Oncol 8:677–688CrossRefPubMedGoogle Scholar
  5. 5.
    Serdons K, Verbruggen A, Bormans GM (2009) Developing new molecular imaging probes for PET. Methods 48:104–111CrossRefPubMedGoogle Scholar
  6. 6.
    Acton PD, Zhou R (2005) Imaging reporter genes for cell tracking with PET and SPECT. The Quarterly Journal of Nuclear Medicine and Molecular Imaging: Official Publication of the Italian Association of Nuclear Medicine 49:349–360Google Scholar
  7. 7.
    Gelovani Tjuvajev J, Blasberg RG (2003) In vivo imaging of molecular-genetic targets for cancer therapy. Cancer Cell 3:327–332CrossRefPubMedGoogle Scholar
  8. 8.
    Herschman HR (2004) PET reporter genes for noninvasive imaging of gene therapy, cell tracking and transgenic analysis. Crit Rev Oncol Hematol 51:191–204CrossRefPubMedGoogle Scholar
  9. 9.
    McCracken MN, Tavare R, Witte ON, Wu AM (2016) Advances in PET detection of the antitumor T cell response. Adv Immunol 131:187–231CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Saral R, Burns WH, Laskin OL, Santos GW, Lietman PS (1981) Acyclovir prophylaxis of herpes-simplex-virus infections. N Engl J Med 305:63–67CrossRefPubMedGoogle Scholar
  11. 11.
    Tiberghien P, Reynolds CW, Keller J et al (1994) Ganciclovir treatment of herpes simplex thymidine kinase-transduced primary T lymphocytes: an approach for specific in vivo donor T-cell depletion after bone marrow transplantation? Blood 84:1333–1341PubMedGoogle Scholar
  12. 12.
    Black ME, Newcomb TG, Wilson HM, Loeb LA (1996) Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy. Proc Natl Acad Sci U S A 93:3525–3529CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Blumenthal M, Skelton D, Pepper KA, Jahn T, Methangkool E, Kohn DB (2007) Effective suicide gene therapy for leukemia in a model of insertional oncogenesis in mice. Molecular therapy: The Journal of the American Society of Gene Therapy 15:183–192CrossRefGoogle Scholar
  14. 14.
    Tjuvajev JG, Stockhammer G, Desai R et al (1995) Imaging the expression of transfected genes in vivo. Cancer Res 55:6126–6132PubMedGoogle Scholar
  15. 15.
    Gambhir SS, Barrio JR, Wu L et al (1998) Imaging of adenoviral-directed herpes simplex virus type 1 thymidine kinase reporter gene expression in mice with radiolabeled ganciclovir. Journal of nuclear medicine: official publication, Society of Nuclear Medicine 39:2003–2011Google Scholar
  16. 16.
    Tjuvajev JG, Avril N, Oku T et al (1998) Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography. Cancer Res 58:4333–4341PubMedGoogle Scholar
  17. 17.
    Penuelas I, Boan JF, Marti-Climent JM et al (2002) A fully automated one pot synthesis of 9-(4-[18F]fluoro-3-hydroxymethylbutyl) guanine for gene therapy studies. Molecular imaging and biology: MIB: The Official Publication of the Academy of Molecular Imaging 4:415–424CrossRefGoogle Scholar
  18. 18.
    Yaghoubi S, Barrio JR, Dahlbom M et al (2001) Human pharmacokinetic and dosimetry studies of [(18)F]FHBG: a reporter probe for imaging herpes simplex virus type-1 thymidine kinase reporter gene expression. Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine 42:1225–1234Google Scholar
  19. 19.
    Le LQ, Kabarowski JH, Wong S, Nguyen K, Gambhir SS, Witte ON (2002) Positron emission tomography imaging analysis of G2A as a negative modifier of lymphoid leukemogenesis initiated by the BCR-ABL oncogene. Cancer Cell 1:381–391CrossRefPubMedGoogle Scholar
  20. 20.
    Hustinx R, Shiue CY, Alavi A et al (2001) Imaging in vivo herpes simplex virus thymidine kinase gene transfer to tumour-bearing rodents using positron emission tomography and. Eur J Nucl Med 28:5–12CrossRefPubMedGoogle Scholar
  21. 21.
    Su H, Forbes A, Gambhir SS, Braun J (2004) Quantitation of cell number by a positron emission tomography reporter gene strategy. Molecular imaging and biology: MIB: the Official Publication of the Academy of Molecular Imaging 6:139–148CrossRefGoogle Scholar
  22. 22.
    Johnson M, Karanikolas BD, Priceman SJ et al (2009) Titration of variant HSV1-tk gene expression to determine the sensitivity of 18F-FHBG PET imaging in a prostate tumor. Journal of nuclear medicine: Official Publication, Society of Nuclear Medicine 50:757–764CrossRefGoogle Scholar
  23. 23.
    Moolten FL, Wells JM, Heyman RA, Evans RM (1990) Lymphoma regression induced by ganciclovir in mice bearing a herpes thymidine kinase transgene. Hum Gene Ther 1:125–134CrossRefPubMedGoogle Scholar
  24. 24.
    Gambhir SS, Bauer E, Black ME et al (2000) 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 U S A 97:2785–2790CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Davis HE, Morgan JR, Yarmush ML (2002) Polybrene increases retrovirus gene transfer efficiency by enhancing receptor-independent virus adsorption on target cell membranes. Biophys Chem 97:159–172CrossRefPubMedGoogle Scholar
  26. 26.
    Loening AM, Gambhir SS (2003) AMIDE: a free software tool for multimodality medical image analysis. Mol Imaging 2:131–137CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Tiscornia G, Singer O, Verma IM (2006) Production and purification of lentiviral vectors. Nat Protoc 1:241–245CrossRefPubMedGoogle Scholar
  28. 28.
    Ponde DE, Dence CS, Schuster DP, Welch MJ (2004) Rapid and reproducible radiosynthesis of [18F] FHBG. Nucl Med Biol 31:133–138CrossRefPubMedGoogle Scholar
  29. 29.
    Alauddin MM, Conti PS (1998) 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 25:175–180CrossRefPubMedGoogle Scholar
  30. 30.
    Shiue GG, Shiue CY, Lee RL et al (2001) A simplified one-pot synthesis of 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine([18F]FHPG) and 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG) for gene therapy. Nucl Med Biol 28:875–883CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Melissa N. McCracken
    • 1
    • 2
    • 3
  1. 1.Institute for Stem Cell Biology and Regenerative MedicineStanford University School of MedicineStanfordUSA
  2. 2.Ludwig Center for Cancer Stem Cell Research and MedicineStanford University School of MedicineStanfordUSA
  3. 3.Stanford Cancer InstituteStanford University School of MedicineStanfordUSA

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