Advertisement

Imaging DNA synthesis with [18F]FMAU and positron emission tomography in patients with cancer

  • Haihao Sun
  • Andrew Sloan
  • Thomas J. Mangner
  • Ulka Vaishampayan
  • Otto Muzik
  • Jerry M. Collins
  • Kirk Douglas
  • Anthony F. ShieldsEmail author
Molecular Imaging

Abstract

Purpose

FMAU (1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)thymine) is a thymidine analog that can be phosphorylated by thymidine kinase and incorporated into DNA. This first-in-human study of [18F]FMAU was conducted as a pilot in patients to determine its biodistribution and suitability for imaging DNA synthesis in tumors using positron emission tomography (PET).

Methods

Fourteen patients with diverse cancers (brain, prostate, colorectal, lung, and breast) were imaged with [18F]FMAU. We obtained dynamic PET images for 60 min and a whole-body image. Blood and urine samples were analyzed by high-performance liquid chromatography to measure metabolites and clearance.

Results

Active tumors in the breast, brain, lung and prostate were clearly visualized with standardized uptake values (SUVs) of 2.19, 1.28, 2.21, and 2.27–4.42, respectively. Unlike with other tracers of proliferation, low uptake of [18F]FMAU was seen in the normal bone marrow (SUVmean 0.7), allowing visualization of metastatic prostate cancer (SUV 3.07). Low background was also observed in the brain, pelvis, and thorax, aside from heart uptake (SUV 3.36–8.78). In the abdomen, increased physiological uptake was seen in the liver (SUV 10.07–20.88) and kidneys (SUV 7.18–15.66) due to metabolism and/or excretion, but the urinary bladder was barely visible (SUVmean 2.03). On average, 95% of the activity in the blood was cleared within 10 min post injection and an average of 70% of the activity in the urine was intact FMAU at 60 min post injection.

Conclusion

Tumors in the brain, prostate, thorax, and bone can be clearly visualized with FMAU. In the upper abdomen, visualization is limited by the physiological uptake by the liver and kidneys.

Keywords

FMAU PET Proliferation 

Notes

Acknowledgments

The authors thank Dr. Elizabeth Dawe for veterinary assistance, and Theresa A. Jones, CNMT, for her expert technical assistance in performing the PET studies. This work was partially supported by funding from the National Cancer Institute grants CA 83131 and CA 82645 and the U.S. Department of Defense award W81XWH-04-1-0140.

References

  1. 1.
    Shields A. Monitoring treatment response. In: Wahl R, editor. Principles and practice of positron emission tomography. Philadelphia: Lippincott; 2002. p. 252–67.Google Scholar
  2. 2.
    Shields AF, Mankoff DA, Link JM, Graham MM, Eary JF, Kozawa M, et al. [11C]Thymidine and FDG to measure therapy response. J Nucl Med 1998;39:1757–62.PubMedGoogle Scholar
  3. 3.
    Eary JF, Mankoff DA, Spence AM, Berger MS, Olshen A, Link JM, et al. 2-[C-11]thymidine imaging of malignant brain tumors. Cancer Res 1999;59(3):615–21.PubMedGoogle Scholar
  4. 4.
    Shields A, Grierson J, Dohmen B, Machulla H-J, Stayanoff J, Lawhorn-Crews J, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 1998;4:1334–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Aboagye EO, Saleem A, Cunningham VJ, Osman S, Price PM. Extraction of 5-fluorouracil by tumor and liver: a noninvasive positron emission tomography study of patients with gastrointestinal cancer. Cancer Res 2001;61(13):4937–41.PubMedGoogle Scholar
  6. 6.
    Conti P, Alauddin M, Fissekis J, Schmall B, Watanabe K. 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(6):783–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Mangner T, Klecker R, Anderson L, Shields A. Synthesis of 2′-[18F]fluoro-2′-deoxy-β-D-arabinofuranosyl nucleotides, [18F]FAU, [18F]FMAU, [18F]FBAU and [18F]FIAU, as potential pet agents for imaging cellular proliferation. Nucl Med Biol 2003(30):215–24.CrossRefPubMedGoogle Scholar
  8. 8.
    Sun H, Mangner T, Collins J, Muzik O, Douglas K, Shields A. Imaging DNA synthesis in vivo with [F-18]FMAU and positron emission tomography. J Nucl Med (in press).Google Scholar
  9. 9.
    Fanucchi MP, Leyland-Jones B, Young CW, Burchenal JH, Watanabe KA, Fox JJ. Phase I trial of 1-(2′-deoxy-2′-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU). Cancer Treat Rep 1985;69(1):55–9.PubMedGoogle Scholar
  10. 10.
    Abbruzzese JL, Schmidt S, Raber MN, Levy JK, Castellanos AM, Legha SS, et al. Phase I trial of 1-(2′-deoxy-2′-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU) terminated by severe neurologic toxicity. Invest New Drugs 1989;7(2–3):195–201.CrossRefPubMedGoogle Scholar
  11. 11.
    Wang H, Oliver P, Nan L, Wang S, Wang Z, Rhie JK, 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(5):419–24.CrossRefPubMedGoogle Scholar
  12. 12.
    Lewis W, Levine ES, Griniuviene B, Tankersley KO, Colacino JM, Sommadossi JP, et al. Fialuridine and its metabolites inhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts. Proc Natl Acad Sci U S A 1996;93(8):3592–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Lu L, Samuelsson L, Bergstrom M, Sato K, Fasth KJ, Langstrom B. Rat studies comparing 11C-FMAU, 18F-FLT, and 76Br-BFU as proliferation markers. J Nucl Med 2002;43(12):1688–98.PubMedGoogle Scholar
  14. 14.
    Kierdaszuk B, Krawiec K, Kazimierczuk Z, Jacobsson U, Johansson NG, Munch-Petersen B, et al. Substrate/inhibitor properties of human deoxycytidine kinase (dCK) and thymidine kinases (TK1 and TK2) towards the sugar moiety of nucleosides, including O′-alkyl analogues. Nucleosides Nucleotides 1999;18(8):1883–903.Google Scholar
  15. 15.
    Knecht W, Petersen GE, Munch-Petersen B, Piskur J. Deoxyribonucleoside kinases belonging to the thymidine kinase 2 (TK2)-like group vary significantly in substrate specificity, kinetics and feed-back regulation. J Mol Biol 2002;315(4):529–40.CrossRefPubMedGoogle Scholar
  16. 16.
    Collins JM, Klecker RW, Katki AG. Suicide prodrugs activated by thymidylate synthase: rationale for treatment and noninvasive imaging of tumors with deoxyuridine analogues. Clin Cancer Res 1999;5(8):1976–81.PubMedGoogle Scholar
  17. 17.
    Sun H, Collins JM, Mangner TJ, Muzik O, Shields AF. Imaging [18F]FAU [1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl) uracil] in dogs. Nucl Med Biol 2003;30(1):25–30.CrossRefPubMedGoogle Scholar
  18. 18.
    de Vries EF, van Waarde A, Harmsen MC, Mulder NH, Vaalburg W, Hospers GA. [11C]FMAU and [18F]FHPG as PET tracers for herpes simplex virus thymidine kinase enzyme activity and human cytomegalovirus infections. Nucl Med Biol 2000;27(2):113–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Hara T, Kosaka N, Kishi H. PET imaging of prostate cancer using carbon-11-choline. J Nucl Med 1998;39(6):990–5.PubMedGoogle Scholar
  20. 20.
    Price DT, Coleman RE, Liao RP, Robertson CN, Polascik TJ, DeGrado TR. Comparison of [18F]fluorocholine and [18F]fluorodeoxyglucose for positron emission tomography of androgen dependent and androgen independent prostate cancer. J Urol 2002;168(1):273–80.CrossRefPubMedGoogle Scholar
  21. 21.
    Goethals P, Lameire N, van Eijkeren M, Kesteloot D, Thierens H, Dams R. [Methyl-carbon-11] thymidine for in vivo measurement of cell proliferation. J Nucl Med 1996;37(6):1048–52.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Haihao Sun
    • 1
  • Andrew Sloan
    • 1
  • Thomas J. Mangner
    • 1
  • Ulka Vaishampayan
    • 1
  • Otto Muzik
    • 1
  • Jerry M. Collins
    • 2
  • Kirk Douglas
    • 1
  • Anthony F. Shields
    • 1
    Email author
  1. 1.Karmanos Cancer Institute, Departments of Medicine, Radiology and PediatricsWayne State UniversityDetroitUSA
  2. 2.Food and Drug AdministrationRockvilleUSA

Personalised recommendations