Advertisement

Tracking Docetaxel-Induced Cellular Proliferation Changes in Prostate Tumor-Bearing Mice with 18F-FMAU PET

  • Hossein Jadvar
    Correspondence
    Address correspondence to: H.J.
    Affiliations
    Molecular Imaging Center, Department of Radiology, USC Keck School of Medicine, University of Southern California, 2250 Alcazar Street, CSC 102, Los Angeles, California, 90033, (H.J., R.P., I.V., K.C.)
    Search for articles by this author
  • Ryan Park
    Affiliations
    Molecular Imaging Center, Department of Radiology, USC Keck School of Medicine, University of Southern California, 2250 Alcazar Street, CSC 102, Los Angeles, California, 90033, (H.J., R.P., I.V., K.C.)
    Search for articles by this author
  • Ivetta Vorobyova
    Affiliations
    Molecular Imaging Center, Department of Radiology, USC Keck School of Medicine, University of Southern California, 2250 Alcazar Street, CSC 102, Los Angeles, California, 90033, (H.J., R.P., I.V., K.C.)
    Search for articles by this author
  • Kai Chen
    Affiliations
    Molecular Imaging Center, Department of Radiology, USC Keck School of Medicine, University of Southern California, 2250 Alcazar Street, CSC 102, Los Angeles, California, 90033, (H.J., R.P., I.V., K.C.)
    Search for articles by this author
Published:September 29, 2022DOI:https://doi.org/10.1016/j.acra.2022.09.005

      Objectives

      The aim of this exploratory preclinical study was to evaluate the efficacy of 18F-FMAU PET in quantitatively measuring cellular proliferation changes in response to a chemotherapeutic agent in experimental prostate cancer models.

      Methods and Materials

      Docetaxel (DTX) ‒ a standard therapy agent in castrate-resistant metastatic prostate cancer was used as the chemotherapy drug. Athymic male nu/nu mice were inoculated with PC-3 cells in the right flank. After the tumor diameter reached 5 mm, DTX (24 mg/kg) was injected intravenously twice a week, whereas the control group was intravenously administered with saline. The tumor size and body weight were monitored, and longitudinal PET scans were acquired with 18F-FMAU to evaluate tumor cellular proliferation. 18F-FMAU PET scans were performed at 2 hours post-injection of 18F-FMAU on days 0, 11, 18, and 22. Biodistribution studies were carried out after the PET scan on day 22.

      Results

      Consecutive administrations of DTX were effective in inhibiting PC-3 tumor growth compared to the control group. For PET imaging, PC-3 tumor uptake of 18F-FMAU in the DTX group was increased significantly from 3.09 ± 0.60 %ID/g (day 0) to 5.32 ± 0.37 %ID/g (day 22), whereas the 18F-FMAU tumor update in the control group remained relatively stable on day 0 (2.37 ± 0.51 %ID/g) vs. day 22 (1.83 ± 0.22 %ID/g). The tumor-to-muscle uptake ratio of 18F-FMAU was increased from 2.63 ± 0.20 (day 0) to 5.91 ± 1.1 (day 22) in the DTX group. On day 22, no statistical significance was observed in the tumor-to-muscle uptake ratio of 18F-FMAU in the DTX group vs. the control group. The tumor-to-liver uptake ratio of 18F-FMAU was also similar on day 22 in the DTX group (4.29 ± 0.09) vs. the control group (3.83 ± 0.59).

      Conclusion

      18F-FMAU uptake in implanted PC-3 tumors increases with DTX despite inhibiting tumor growth. Further investigation is needed to decipher the underlying biological mechanism of this apparent flare effect and its relation to the predictability of tumor response to DTX.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Academic Radiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      REFERENCES

        • Bading JR
        • Shields AF.
        Imaging of cell proliferation: status and prospects.
        J Nucl Med. 2008; 49: 64S-80S
        • Mankoff DA
        • Shields AF
        • Krohn KA.
        PET imaging of cellular proliferation.
        Radiol Clin North Am. 2005; 43: 153-167
        • Mach RJ
        • Dehdashti F
        • Wheeler KT.
        PET radiotracers for imaging the proliferative status of solid tumors.
        PET Clin. 2009; 4: 1-15
        • Krohn KA
        • Mankoff DA
        • Eary JF.
        Imaging cellular proliferation as a measure of response to therapy.
        J Clin Pharmacol. 2001; : 96S-103S
        • Munch-Petersen B
        • Cloos L
        • Jensen HK
        • et al.
        Human thymidine kinase I. Regulation in normal and malignant cells.
        Adv Enzym Regul. 1995; 35: 69-89
        • Kairemo K
        • Ravizzini GC
        • Macapinlac HA
        • et al.
        An assessment of early response to targeted therapy via molecular imaging: a pilot study of 3′-deoxy-3′[18F]-fluorothymidine positron emission tomography 18F-FLT PET/CT in prostate adenocarcinoma.
        Diagnostics. 2017; 7: 20
        • Wang H
        • Oliver P
        • Nan L
        • et al.
        Radiolabeled 2′-fluorodeoxyuracil-beta-D-arabinofuranoside (FAU) and 2′-fluoro-5-methyldeoxyuracil-beta -D-arabinofuranoside (FMAU) as tumor-imaging agents in mice.
        Cancer Chemother Pharmacol. 2002; 49: 419-424
        • Schwartz JL
        • Tamura Y
        • Jordan R
        • et al.
        Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine an thymidine analogs.
        J Nucl Med. 2003; 44: 2027-2032
        • Tehrani OS
        • Douglas KA
        • Lawhorn-Crews JM
        • et al.
        Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2.
        Eur J Nucl Med Mol Imaging. 2008; 35: 1480-1488
        • Conti PS
        • Alauddin MM
        • Fissekis JR
        • et al.
        Synthesis of 2′-fluoro-5-[11C]-methyl-1-beta-D-arabinofuranosyluracil ([11C]-FMAU): a potential nucleoside analog for in vivo study of cellular proliferation with PET.
        Nucl Med Biol. 1995; 22: 783-789
        • Sun H
        • Mangner TJ
        • Collins JM
        • et al.
        Imaging DNA synthesis in vivo with 18F-FMAU and PET.
        J Nucl Med. 2005; 46: 292-296
        • Manger TJ
        • Klecker RW
        • Anderson L
        • Shields AF.
        Synthesis of 2’-deoxy-2’-[18F]fluoro-beta-D-arabinofuranosyl nucleosides, [18F]FAU, [18F]FMAU, [18F]FBAU and [18F]FIAU, as potential PET agents for imaging cellular proliferation: synthesis of [18F]labeled FAU, FMAU, FBAU, FIAU.
        Nucl Med Biol. 2003; 30: 215-224
        • Chen K
        • Li Z
        • Conti PS.
        Microwave-assisted one-pot radiosynthesis of 2′-deoxy-2′-[18F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ([18F]-FMAU).
        Nucl Med Biol. 2012; 39: 1019-1025
        • Li J
        • Van Valkenburgh J
        • Conti PS
        • Chen K.
        Exploring solvent effects in the radiosynthesis of 18F-labeled thymidine analogues toward clinical translation for positron emission tomography imaging.
        ACS Pharmacol Transl Sci. 2021; 4: 266-275
        • Armstrong AJ.
        New treatments for men with castration-resistant prostate cancer: can we move from small steps to giant leaps?.
        Eur Urol. 2014; 65: 300-302
        • Ballas LK
        • de Castro Abreu AL
        • Quinn DI.
        What medical, urologic, and radiation oncologists want from molecular imaging of prostate cancer.
        J Nucl Med. 2016; 57: 6S-12S
        • Fanti S
        • Goffin K
        • Hadaschik BA
        • et al.
        Consensus statements on PSMA PET/CT response assessment criteria in prostate cancer.
        Eur J Nucl Med Mol Imaging. 2021; 48: 469-476
        • McHugh CI
        • Lawhon-Crews JM
        • Modi D
        • et al.
        Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: 18F-FAU, 18F-FMAU, and 18F-FLT.
        Cancer Imaging. 2016; 16: 34
        • Mankoff DA
        • Dehdashti F
        • Shileds AF.
        Characterizing tumors using metabolic imaging: PET imaging of cellular proliferation and steroid receptors.
        Neoplasia. 2000; 2: 71-88
        • Kluza J
        • Marchetti P
        • Gallego MA
        • et al.
        Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells.
        Oncogene. 2004; 23: 7018-7030
        • van Waarde A
        • Elsinga PH.
        Proliferation markers for the differential diagnosis of tumor and inflammation.
        Curr Pharm Dis. 2008; 14: 3326-3339