Integrated Systems and Technologies Preclinical Evidence That 3 0 -Deoxy-3 0 - [ 18 F]Fluorothymidine PET Can Visualize Recovery of Hematopoiesis after Gemcitabine Chemotherapy Sonja Schelhaas 1 , Annelena Held 1 , Nicole B€ aumer 2 , Thomas Viel 1 , Sven Hermann 1 , Carsten M€ uller-Tidow 2,3 , and Andreas H. Jacobs 1,4 Abstract Molecular imaging with the PET tracer 3 0 -deoxy-3 0 - [ 18 F]fluorothymidine ([ 18 F]FLT) allows assessment of the pro- liferative state of organs in vivo. Although used primarily in the oncology clinic, it can also shed light on the proliferation of other tissues, as demonstrated here for monitoring hematopoi- etic organs that recover after myelosuppressive chemotherapy. In the NMRI nude mouse model, we observed up to a 4.5-fold increase in [ 18 F]FLT uptake in bone marrow and spleen on days 2, 3, and 5 after treatment with gemcitabine, a chemothera- peutic agent that is powerfully myelosuppressive in the model. Specifically, we observed (i) a reduced spleen weight; (ii) reduced bone marrow cell counts and proliferation (BrdUrd flow cytometry, spleen IHC; 6 hours/day 1); and (iii) reduced leukocytes in peripheral blood (day 5). In conclusion, our results show how [ 18 F]FLT PET can provide a powerful tool to noninvasively visualize the proliferative status of hematopoi- etic organs after myelosuppressive therapy. Cancer Res; 76(24); 7089–95. Ó2016 AACR. Introduction Chemotherapy of malignant cancers is frequently accompanied by several side effects. One of the most common adverse effects is the impact of the chemotherapeutic agent on bone marrow cells, subsequently affecting the numbers of white blood cells (leuko- penia or neutropenia; ref. 1), platelets (thrombocytopenia; ref. 2), and red blood cells (anemia; ref. 3). For instance, neutropenia may result in secondary infections, ultimately leading to the death of the patient. It is well recognized that the hematopoietic organs are able to regenerate after insult due to the presence of hemato- poietic stem cells. Therefore, it is of importance, not to employ chemo- or radiotherapy in the phase of recovery of the hemato- poietic organs, as this might result in the destruction of hemato- poietic stem cells with permanent impact on the blood compo- sition. A range of models exists that describes the relation of the application of a chemotherapeutic agent and the impact on bone marrow and other tissues (4). To know this relation is of crucial importance for dosing and timing of a chemotherapeutic drug. Unfortunately, changes in the blood cellular components, which are easily measurable in clinical routine, are not directly timely linked to changes in the proliferation of hematopoietic stem cells. PET is an attractive tool to noninvasively and longitudinally visualize molecular changes within a living organism. It is widely used in the fields of oncology, cardiology, and neuro- science. Depending on the radiotracer used, it can monitor specific molecular events. 3 0 -Deoxy-3 0 -[ 18 F]fluorothymidine ([ 18 F]FLT) is a thymidine analogue that is transported into cells primarily via the human equilibrative nucleoside trans- porter 1 (hENT1; ref. 5). Within a cell, it is phosphorylated by thymidine kinase 1 (TK1), which results in trapping of the tracer. Hence, accumulation of [ 18 F]FLT resembles the thymi- dine salvage pathway and therefore proliferation. An alternative thymidine-to-DNA pathway is the de novo synthesis pathway, with the key enzyme thymidylate synthase (TS). In various studies, [ 18 F]FLT has been proven to be useful in monitoring response to anticancer treatments (6, 7). There are only limited reports on [ 18 F]FLT PET imaging concentrating on other pro- liferative tissues than tumors like the hematopoietic compart- ments. One study showed that [ 18 F]FLT PET can visualize bone marrow recovery after bone marrow transplantation in rats (8), and Ye and colleagues described that [ 18 F]FLT PET is capable of imaging the proliferative state of cells in aortic plaques and hematopoietic organs in mice, rabbit, and men (9). Here, we employed [ 18 F]FLT PET to noninvasively and longi- tudinally visualize the recovery of hematopoietic organs after chemotherapeutic treatment with gemcitabine in a mouse model. 1 European Institute for Molecular Imaging (EIMI), Westf€ alische Wilhelms-Uni- versit€ at (WWU) M€ unster, M€ unster, Germany. 2 Department of Medicine A, Molecular Hematology and Oncology, University Hospital of M€ unster, M€ unster, Germany. 3 Department of Internal Medicine, Hematology and Oncology, Uni- versity of Hospital Halle, Halle, Germany. 4 Department of Geriatric Medicine, Johanniter Hospital, Bonn, Germany. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Current address for A. Held: Department of Orthopedic Surgery, Otto-von- Guericke University, Magdeburg, Germany; and current address for T. Viel: PARCC INSERM-U970, Universit e Paris Descartes, Paris, France. Corresponding Author: Andreas H. Jacobs, Westf€ alische Wilhelms-Universit€ at, Waldeyerstr. 15, M€ unster 48149, Germany. Phone: 49-251-83-49300; Fax: 49- 251-83-49313; E-mail: ahjacobs@uni-muenster.de doi: 10.1158/0008-5472.CAN-16-1478 Ó2016 American Association for Cancer Research. Cancer Research www.aacrjournals.org 7089 on May 23, 2020. © 2016 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst October 20, 2016; DOI: 10.1158/0008-5472.CAN-16-1478