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[18F]FLT is superior to [18F]FDG for predicting early response to antiproliferative treatment in high-grade lymphoma in a dose-dependent manner

  • Nicolas GrafEmail author
  • Ken Herrmann
  • Barbara Numberger
  • Daniela Zwisler
  • Michaela Aichler
  • Annette Feuchtinger
  • Tibor Schuster
  • Hans-Jürgen Wester
  • Reingard Senekowitsch-Schmidtke
  • Christian Peschel
  • Markus Schwaiger
  • Ulrich Keller
  • Tobias Dechow
  • Andreas K. Buck
Original Article

Abstract

Purpose

Positron emission tomography (PET) with the thymidine analogue [18F]fluorothymidine ([18F]FLT) has been shown to detect early response to chemotherapy in high-grade lymphoma. In this preclinical in vitro and in vivo study we compared [18F]FLT to the glucose analogue [18F]fluorodeoxyglucose ([18F]FDG) regarding dose-dependent visualization and prediction of early therapy response.

Methods

Immunodeficient mice bearing human diffuse large B-cell lymphoma (SUDHL-4) xenotransplants were treated intraperitoneally with increasing doses of the cytotoxic agent doxorubicin. Metabolic and antiproliferative effects were assessed 2 days after therapy by [18F]FLT and [18F]FDG PET. Explanted lymphomas were analysed histologically and by immunostaining against Ki67 and caspase 3. In vitro, lymphoma cells were incubated with increasing concentrations of doxorubicin and analysed using the tetrazolium assay, fluorescence-activated cell sorting, and [18F]FLT and [18F]FDG uptake 48 h later.

Results

In vivo, tumour growth was inhibited by doses of doxorubicin ranging from 25 μg to 200 μg. The mean tumour-to-background ratio (TBR) of [18F]FLT on day +2 was significantly reduced in all dose groups compared to control and baseline values and preceded changes in tumour volume. Importantly, there was a significant inverse correlation between reduction in TBR and dose of chemotherapy (r = −0.54, p = 0.021). The mean TBR of [18F]FDG, however, increased after therapy and differed considerably between groups (r = −0.13, p = 0.668). Explanted tumours showed a dose-dependent decrease in the proliferation marker Ki67, but no change in the apoptotic marker caspase 3. In vitro, doxorubicin led to a dose-dependent reduction in cell viability and a decrease in S phase. Lymphoma cells showed a dose-dependent reduction in [18F]FLT uptake, in contrast to a variable and decelerated reduction in [18F]FDG uptake. Thus, the increase in [18F]FDG uptake in vivo presumably reflected nonspecific glucose metabolism of inflammatory cells, as confirmed by histology of explanted lymphomas.

Conclusion

Early responses to dose-dependent antiproliferative treatment in high-grade lymphoma are more accurately visualized with [18F]FLT PET than with [18F]FDG PET.

Keywords

FLT PET FDG PET Lymphoma Dose-dependency Therapy monitoring 

Notes

Acknowledgments

We appreciate the excellent contributions made by our colleague Petra Watzlowik, PhD, and the great support of our the member of technical staff Sybille Reder, Elisabeth Aywanger and Brigitte Dzewas. Supported by the Deutsche Forschungsgemeinschaft (SFB824 to A. Buck and T. Dechow, SFB TRR54 to U. Keller).

Conflicts of interest

None.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Nicolas Graf
    • 1
    • 6
    Email author
  • Ken Herrmann
    • 2
  • Barbara Numberger
    • 2
  • Daniela Zwisler
    • 2
  • Michaela Aichler
    • 3
  • Annette Feuchtinger
    • 3
  • Tibor Schuster
    • 4
  • Hans-Jürgen Wester
    • 2
  • Reingard Senekowitsch-Schmidtke
    • 2
  • Christian Peschel
    • 1
  • Markus Schwaiger
    • 2
  • Ulrich Keller
    • 1
  • Tobias Dechow
    • 1
  • Andreas K. Buck
    • 2
    • 5
  1. 1.Department of Hematology/OncologyTechnische Universität MünchenMunichGermany
  2. 2.Department of Nuclear MedicineTechnische Universität MünchenMunichGermany
  3. 3.Institute of Pathology (Helmholtz Zentrum München)Technische Universität MünchenMunichGermany
  4. 4.Institute of Medical Statistics and EpidemiologyTechnische Universität MünchenMunichGermany
  5. 5.Department of Nuclear MedicineUniversitätsklinikum WürzburgWürzburgGermany
  6. 6.Department of Hematology and OncologySchön Klinik Starnberger SeeBergGermany

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