Imaging Cellular Proliferation in Prostate Cancer with Positron Emission Tomography

Document Type: Review article

Author

Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

10.7508/aojnmb.2015.02.001

Abstract

Prostate cancer remains a major public health problem worldwide. Imaging plays an important role in the assessment of disease at all its clinical phases, including staging, restaging after definitive therapy, evaluation of therapy response, and prognostication. Positron emission tomography with a number of biologically targeted radiotracers has been demonstrated to have potential diagnostic and prognostic utility in the various clinical phases of this prevalent disease. Given the remarkable biological heterogeneity of prostate cancer, one major unmet clinical need that remains is the non-invasive imaging-based characterization of prostate tumors. Accurate tumor characterization allows for image-targeted biopsy and focal therapy as well as facilitates objective assessment of therapy effect. PET in conjunction with radiotracers that track the thymidine salvage pathway of DNA synthesis may be helpful to fulfill this necessity. We review briefly the preclinical and pilot clinical experience with the two major cellular proliferation radiotracers, [18F]-3’-deoxy-3’-fluorothymidine and [18F]-2’-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil in prostate cancer.

Keywords

Main Subjects


 

  1. Jadvar H. Molecular imaging of prostate cancer: PET radiotracers. AJR Am J Roentgenol. 2012; 199:278-91.
  2. Yu CY, Desai B, Ji L, Groshen S, Jadvar H. Comparative performance of PET tracers in biochemical recurrence of prostate cancer: a critical analysis of literature. Am J Nucl Med Mol Imaging. 2014; 4:580-601.
  3. Mankoff DA, Shields AF, Krohn KA. PET imaging of cellular proliferation. Radiol Clin North Am. 2005; 43:153-67.
  4. Couturier O, Leost F, Campone M, Cartlier T, Chatal JF, Hustinx R. Is 3’-deoxy-3’-[18F]fluorothymidine ([18F]-FLT) the next tracer for routine clinical PET after [18F]-FDG? Bull Cancer. 2005; 92:789-98.
  5. Nimmagadda S, Shields AF. The role of DNA synthesis imaging in cancer in the era of targeted therapeutics. Cancer Metastasis Rev. 2008; 27:575- 87.
  6. Bading JR, Shields AF. Imaging of cell proliferation: status and prospects. J Nucl Med. 2008; 49 Suppl 2:64S-80S.
  7. Tehrani OS, Shields AF. PET imaging of proliferation with pyrimdines. J Nucl Med. 2013; 54:903-12.
  8. Shields AF, Mankoff D, Graham MM, Zheng M, Kozawa SM, Link JM, et al. Analysis of 2-carbon-11- thymidine blood metabolites in PET imaging. J Nucl Med. 1996; 37:290-6.
  9. Shields AF, Mankoff DA, Link JM, Graham MM, Eary JF, Kozawa SM, et al. Carbon-11-thymidine and FDG to measure therapy response. J Nucl Med. 1998; 39:1757-62.
  10. Mankoff D, Shields AF, Link JM, Graham MM, Muzi M, Pterson LM, et al. Kinetic analysis of 2-[11C] thymidine PET imaging studies: validation studies. J Nucl Med. 1999; 40:614-24.
  11. Mankoff DA, Shield AF, Graham MM, Link JM, Eary JF, Krohn KA. Kinetic analysis of 2-[carbon- 11] thymidine PET imaging studies: compartmental model and mathematical analysis. J Nucl Med. 1998; 39:1043-55.
  12. Shields AF, Grierson JR, Muzik O, Stayanoff JC, Lawhorn-Crews JM, Obradovich JE, et al. Kinetics of 3’-deoxy-3’-[F- 18]fluorothymidine uptake and retention in dogs. Mol Imaging Biol. 2002 4:83-9.
  13. Shields AF, Briston DA, Chandupatla S, Douglas KA, Lawhorn-Crews J, Collins JM, et al. A simplified analysis of [18F]3’- deoxy-3’-fluorthymidine metabolism and retention. Eur J Nucl Med Mol Imaging. 2005; 32:1269-75.
  14. Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stananoff JC, Lawhorn-Crews JM, et al. Imaging proliferation in vivo with [F- 18]FLT and positron emission tomography. Nat Med. 1998; 4:1334-6.
  15. Grierson JR, Shields AF. Radiosynthesis of 3′-deoxy- 3′-[18F]fluorothymidine: [18F]FLT for imaging of cellular proliferation in vivo. Nucl Med Biol 2000; 27:143-56.
  16. Vesselle H, Grierson J, Peterson LM, Muzi M, Mankoff DA, Krohn KA. 18F-fluorothymidine radiationdosimetry in human PET imaging studies. J Nucl Med. 2003; 44:1482-8.
  17. Kukuk D, Reischl G, Raguin O, Wiehr S, Judenhofer MS, Calaminus C, et al. Assessment of PET tracer uptake in hormone-independent and hormone-dependent xenograft prostate cancer mouse models. J Nucl Med. 2011; 52:1654-63.
  18. Oyama N, Ponde D, Dence C, Kim J, Tai YC, Welch MJ. Monitoring of therapy in androgen dependent prostate tumor model by measuring tumor proliferation. J Nucl Med. 2004; 45:519-25.
  19. Oyama N, Hasegawa Y, Kiyono Y, Kobayashi M, Fujibayashi Y, Ponde DE, et al. Early response assessment in prostate carcinoma by 18F-fluorothymidine following anticancer therapy with docetaxel using preclinical tumor models. Eur J Nucl Med Mol Imaging. 2011; 38:81-9.
  20. 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; 69:55-9.
  21. Tehrani OS, Douglas KA, Lawhorn-Crews JM, Shields AF. Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2. Eur J Nucl Med Mol Imaging. 2008; 35:1480-8.
  22. Conti PS, Alauddin MM, Fissekis JR, Schmall B, Watanabe KA. 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; 22:783-9.
  23. Bading JR, Shahinian AH, Bathija P, Conti PS.Pharmacokinetics of the thymidine analog 2'-fluoro-5-[(14)C]-methyl-1-beta-D-arabinofuranosyluracil ([(14)C]FMAU) in rat prostate tumor cells. Nucl Med Biol 2000; 27:361-8.
  24. 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 Chemo ther Pharmacol. 2002; 49:419-24.
  25. 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; 43:1688-98.
  26. Mangner 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]labelled FAU, FMAU, FBAU, FIAU. Nucl Med Biol. 2003; 30(3):215-24.
  27. de Vries EF, van Waarde A, Harmsen MC, Mulder NH, Vaaburg W, Hospers GA. [(11)C]FMAU and [(18)F]FHPG as PET tracers for herpes simplex virus thymidine kinase enzyme activity and human cytomegalovirus infections. Nucl Med Biol. 2000; 27:113-9.
  28. Alauddin MM, Shahinian A, Gordon EM, Conti PS. Evaluation of 2’-deoxy-2’- fluoro-5-methyl-1-beta- D-arabinofurasyluracil as a potential gene imaging agent for HSV-tk expression in vivo. Mol Imaging. 2002; 1:74-81.
  29. Alauddin MM, Shahinian A, Park R, Tohme M, Fissekis JD, Conti PS. Synthesis and evaluation of 2’-deoxy-2’-18F-fluoro-5-fluoro-1-beta-D-arabinofuranosyluracil as a potential PET imaging agent for suicide gene expression. J Nucl Med. 2004; 45:2063-9.
  30. Kang KW, Min JJ, Chen X, Gambhir SS. Comparison of [14C]FMAU, [3H]FEAU, [14C]FIAU, and [3H] PCV for monitoring reporter gene expression of wild type and mutant herpes simplex virus type I thymidine kinase in cell culture. Mol Imaging Biol. 2005; 7:296-303.
  31. Li Z, Cai H, Conti PS. Automated synthesis of 2’-deoxy-2’-[18F]fluoro-5-methyl- 1-b-D-arabinofuranosyluracil ([18F]-FMAU) using a one reactor radiosynthesis module. Nucl Med Biol. 2011; 38:201-6.
  32. Bading JR, Shahinian AH, Vail A, Bathija P, Koszalka GW, Koda RT, et al. Pharmacokinetics of the thymidine analog 2’-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (FMAU) in tumor bearing rats. Nucl Med Biol. 2004; 31:407-18.
  33. Conti PS, Bading JR, Mouton PP, Links JM, Alauddin MM, Fissekis JD, et al. In vivo measurement of cell proliferation in canine brain tumor using C-11- labeled FMAU and PET. Nucl Med Biol. 2008; 35(1):131-41.
  34. Tehrani OS, Muzik O, Heilbrun LK, Douglas KA, Lawhorn-Crews JM, Sun H, et al. Tumor imaging using 1-(2’-deoxy-18Ffluoro-beta-D-arabinofuranosyl) thymine and PET. J Nucl Med. 2007; 48:1436-41.
  35. Nishii R, Volgia AY, Mawlawi O, Mukhopadhyay U, Pal A, Bommann W, et al. Evaluation of 2’-deoxy-2’-[(18)F]fluoro-5- methyl-1-beta-L:- arabinofuranosyluracil ([(18)F]-L:-FMAU) as a PET imaging agent for cellular proliferation: comparison with [(18)F]-D:-FMAU and [(18)F]FLT. Eur J Nucl Med Mol Imaging. 2008; 35:990-8.
  36. Sun H, Mangner TJ, Collins JM, Muzik O, Douglas K, Shields AF. Imaging DNA synthesis in vivo with 18F-FMAU and PET. J Nucl Med 2005; 46(2):292-6.
  37. Shields AF. Positron emission tomography measurement of tumor metabolism and growth: its expanding role in oncology. Mol Imaging Biol. 2006; 8:141-50.
  38. Jadvar H, Yap LP, Park R, Li Z, Chen K, Hughes L, et al. [18F]-2’-fluoro-5-methyl-1-beta- Darabinofuranosyluracil (18F-FMAU) in prostate cancer: initial preclinical observations. Mol Imaging. 2012; 11(5):426-32.
  39. Doeg KA, Polomski LL, Doeg LH. Androgen control of mitochondrial and nuclear DNA synthesis in male sex accessory tissue of castrate rats. Endocrinology. 1972; 90:1633-8.
  40. Sun H, Sloan A, Mangner TJ, Vaishamayan U, Muzik O, Collins JM, et al. Imaging DNA synthesis with [18F]FMAU and positron emission tomography in patients with cancer. Eur J Nucl Med Mol Imaging. 2005; 32:15-22.
  41. Alauddin MM, Shahinian A, Gordon EM, Conti PS. Direct comparison of radiolabeled probes FMAU, FHBG, and FHPG as PET imaging agents for HSV1- tk expression in a human breast cancer model. Mol Imaging. 2004; 3:76-84.
  42. Cai H, Li Z, Conti PS. The improved syntheses of 5-substituited 2’-[18F]fluoro-2’-deoxy-arabinofuranosyluracil derivatives ([18F] FAU, [18F] FEAU, [18F] FFAU, [18F] FCAU, [18F] FBAU and [18F] FIAU) using a multistep one-pot strategy. Nucl Med Biol. 2011; 38:659-66.