Preclinical Evidence That 3′-Deoxy-3′-[18F]Fluorothymidine PET Can Visualize Recovery of Hematopoiesis after Gemcitabine Chemotherapy

Abstract

Molecular imaging with the PET tracer 3'-deoxy-3'-[F]fluorothymidine ([F]FLT) allows assessment of the proliferative 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 hematopoietic organs that recover after myelosuppressive chemotherapy. In the NMRI nude mouse model, we observed up to a 4.5-fold increase in [F]FLT uptake in bone marrow and spleen on days 2, 3, and 5 after treatment with gemcitabine, a chemotherapeutic 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 [F]FLT PET can provide a powerful tool to noninvasively visualize the proliferative status of hematopoietic organs after myelosuppressive therapy. Cancer Res; 76(24); 7089-95. ©2016 AACR.

Dual Targeting of Aurora Kinases with AMG 900 Exhibits Potent Preclinical Activity Against Acute Myeloid Leukemia with Distinct Post-Mitotic Outcomes

“…5E, noted by the arrowheads). Skeletal [ 18 F]FLT signal decreased within three days after the initial flare event, suggesting the flare may have resulted from a transient pulse of proliferation associated with bone marrow recovery (40) or alternatively, may have resulted from a drug induced cell-cycle synchronization of remaining viable cancer cells.…”

“…In order to correlate the anti-tumor effects of AMG 900 more directly, we assessed active DNA replication (S-phase) fraction using radiotracer [ 18 F]FLT-PET in skeletal tissue. Factors that influence [ 18 F]FLT-PET signal output after AKI treatment may include differences in proliferation rates between bone marrow and AML cells, thymidine kinase 1 expression, and the level of polyploidization (40, 47). With those stated factors, we clearly demonstrated AMG 900 reduced skeletal [ 18 F]FLT signal during the treatment phase followed by an [ 18 F]FLT flare event after treatment cessation, which may have resulted from bone marrow recovery and/or AML cells re-entering S-phase.…”