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Imaging Proliferation to Monitor Early Response of Lymphoma to Cytotoxic Treatment

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Abstract

Purpose

Positron emission tomography with the thymidine analogue 3′-deoxy-3′-[18F]fluorothymidine (FLT) has been reported to closely reflect lymphoma proliferation in vivo. In this preclinical study, we have investigated if FLT can also be utilized for imaging therapy-induced alterations of the nucleoside metabolism and if FLT is a surrogate marker for early response to cytotoxic treatment.

Materials and Methods

Immunodeficient mice bearing high-grade lymphoma xenotransplants were treated with the cytotoxic agent doxorubicin (day 0). In the time course of day +1 to +9, antiproliferative effects were assessed non-invasively with FLT-PET and correlated to changes of the proliferation fraction and induction of apoptosis, as assessed by immunohistochemistry.

Results

Tumor growth in untreated animals was significantly higher than in treated animals. In FLT-PET scans, these observations correlated with a significant decrease of tumor-to-background ratio in the therapy group already at day 1. Likewise, median tumor-to-muscle ratio of FLT uptake already declined at day 1. The proliferation fraction assessed by Ki-67 immunohistochemistry decreased after chemotherapy, while activated caspase 3 increased, suggesting both cell cycle arrest and induction of apoptosis as underlying mechanisms of the observed PET-signal alterations.

Conclusion

In a lymphoma xenotransplant model, we show that positron emission tomography using the proliferation marker FLT is suitable to detect early response to cytotoxic treatment. A significant decrease of FLT uptake but not tumor growth was detectable already 24 h after therapy and correlated with reduced proliferation and induction of apoptosis. Thus, FLT-PET has a potential for imaging early response to treatment in malignant lymphoma.

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Acknowledgements

We appreciate the excellent contributions made by our colleague Petra Watzlowik PhD and the great support by our technical staff members Sybille Reder, Elisabeth Aywanger, and Brigitte Dzewas. This work was supported by “EMIL” (European Molecular Imaging Laboratories, grant LSHC-CT-2004-503569).

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Authors and Affiliations

  1. Department of Hematology and Oncology, Technische Universität München, Ismaninger Strasse 22, 81675, Munich, Germany

    Nicolas Graf, Ken Herrmann, Christian Peschel & Andreas K. Buck

  2. Department of Nuclear Medicine, Technische Universität München, Munich, Germany

    Jürgen den Hollander, Falko Fend, Reingard Senekowitsch-Schmidtke, Christian Meyer zum Büschenfelde, Markus Schwaiger & Tobias Dechow

  3. Department of Pathology, Universität Tübingen, Tübingen, Germany

    Tibor Schuster

  4. Institute for Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany

    Hans-Jürgen Wester

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  1. Nicolas Graf
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Correspondence to Nicolas Graf.

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Nicolas Graf and Ken Herrmann contributed equally to this work.

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Graf, N., Herrmann, K., den Hollander, J. et al. Imaging Proliferation to Monitor Early Response of Lymphoma to Cytotoxic Treatment. Mol Imaging Biol 10, 349–355 (2008). https://doi.org/10.1007/s11307-008-0162-3

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  • DOI: https://doi.org/10.1007/s11307-008-0162-3

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