Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-cd9895bd7-gxg78 Total loading time: 0 Render date: 2025-01-03T21:04:39.004Z Has data issue: false hasContentIssue false

8 - Cellular Proliferation

Published online by Cambridge University Press:  22 November 2017

By
Hossein Jadvar
Edited by
Hossein Jadvar ,
Heather Jacene  and
Michael Graham
Hossein Jadvar
Affiliation:
Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA
Hossein Jadvar
Affiliation:
University of Southern California Keck School of Medicine, Los Angeles
Heather Jacene
Affiliation:
Dana-Farber Cancer Institute, Boston
Michael Graham
Affiliation:
University of Iowa
Get access

Summary

Controlled proliferation is an important physiologic cellular function. However, uncontrolled cellular proliferation is one of the major hallmarks of cancer. Imaging cellular proliferation may provide valuable diagnostic information about the rate of tumor growth and an opportunity for objective assessment of early response to treatment. Positron emission tomography (PET) in conjunction with radiotracers that track the thymidine salvage pathway of DNA synthesis has been studied extensively for imaging cellular proliferation in cancer. Initially, [11C-methyl]thymidine ([11C-methl]TdR) was synthesized for this purpose but the radiotracer had the major limitation of rapid catabolism. Further research resulted in the development of new radiolabeled analogs that were resistant to catabolism. Those radiotracers labeled with 18F are of particular interest since the longer isotope half-life (110 min) facilitates regional distribution of the tracer without the need for an on-site cyclotron. In this chapter, we briefly describe the experience with two of these radiotracers, [18F]-3’-deoxy-3’-fluorothymidine (18F-FLT) and [18F]-2’-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU) (Figure 8.1).

[18F]-FLT

18F-FLT is the most studied cellular proliferation PET tracer. The radiotracer is phosphorylated by thymidine kinase 1 (TK1), retained in proliferating cells without DNA incorporation, and can be described by a three-compartment model. Normal biodistribution of 18F-FLT demonstrates relatively high uptake in the liver and the bone marrow with urinary bladder receiving the highest dose through renal excretion. Typically 18F-FLT demonstrates lower uptake than 18F-FDG in tumors, although in some anatomic regions, such as the brain, the target-to-background uptake ratio is higher with 18F-FLT than with FDG (given the high physiologic FDG uptake in the brain gray matter). Tehrani and Shields recently summarized the literature on the major clinical investigations with 18F-FLT. These authors caution that not all tumors with high proliferation may show high 18F-FLT uptake due to a variety of factors including the type of cancer and treatment, and biologic processes such as balance between de novo and salvage pathways of DNA synthesis, and balance between increased proliferation rate and decreased apoptosis.

The low 18F-FLT uptake in the normal brain is an advantage that has been investigated for the grading of brain tumors, differentiation of radiation necrosis from residual or recurrent tumor, assessment of treatment response, and in prognostication.

Type
Chapter
Information
Molecular Imaging
An Introduction
 , pp. 36 - 38
Publisher: Cambridge University Press
Print publication year: 2017

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Hanahan, D, Weinberg, RA. Hallmarks of cancer: the next generation. Cell 2011; 144:646–74.CrossRefGoogle ScholarPubMed
2. Mankoff, DA, Shields, AF, Krohn, KA. PET imaging of cellular proliferation. Radiol Clin North Am 2005; 43:153–67.CrossRefGoogle ScholarPubMed
3. 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.Google Scholar
4. 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.CrossRefGoogle ScholarPubMed
5. Krohn, KA, Mankoff, DA, Eary, JF. Imaging cellular proliferation as measure of response to therapy. J Clin Pharmacol 2011; Suppl:96S–103S.Google Scholar
6. Bading, JR, Shields, AF. Imaging of cell proliferation: status and prospects. J Nucl Med 2008; 49 Suppl 2:64S–80S.CrossRefGoogle ScholarPubMed
7. Christman, D, Crawford, EJ, Friedkin, M, Wolf, AP. Detection of DNA synthesis in intact organisms with positron-emitting (methyl-11C)thymidine. Proc Natl Acad Sci USA 1972; 69:988–92.CrossRefGoogle Scholar
8. Shields, AF, Mankoff, DA, Graham, MM, Zheng, M, Lozawa, SM, Link, JM et al. Analysis of 2-carbon-11-thymidine blood metabolites in PET imaging. J Nucl Med 1996; 37:290–6.Google ScholarPubMed
9. Shields, AF, Mankoff, DA, Link, JM, Graham, MM, Eary, JF, Kozawa, SM et al. [11C]Thymidine and FDG to measure therapy response. J Nucl Med 1998; 39:1757–62.Google ScholarPubMed
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.Google ScholarPubMed
11. Mankoff, D, 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.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
14. Shields, AF, Grierson, J, Dohmen, B, 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.CrossRefGoogle Scholar
15. Grierson, JR, Shields, AF. Radiosynthesis of 3’-deoxy-3’-[(18F]fluorothymidine: [(18F)F]FLT for imaging of cellular proliferation in vivo. Nucl Med Biol 2000.CrossRefGoogle Scholar
16. Vesselle, H, Grierson, J, Peterson, LM, Muzi, M, Mankoff, DA, Krohn, KA. 18F-fluorothymidine radiation dosimetry in human PET imaging studies. J Nucl Med 2003; 44:1482–8.Google ScholarPubMed
17. Tehrani, OS, Shields, AF. PET imaging of proliferation with pyrimdines. J Nucl Med 2013; 54:903–12.CrossRefGoogle Scholar
18. Saga, T, Kawashima, H, Araki, N et al. Evaluation of primary brain tumors with FLT-PET: usefulness and limitations. Clin Nucl Med 2006; 31:774–80.CrossRefGoogle ScholarPubMed
19. Tehrani, OS, Douglas, KA, Lawhom-Crews, JM et al. Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2. Eur J Nucl Med Mol Imaging 2008; 35:1480–8.CrossRefGoogle ScholarPubMed
20. Tehrani, OS, Muzik, O, Heilbrun, LK et al. Tumor imaging using 1-(29-deoxy-29-18FFluoro-b-D-Arabinofuranosyl)Thymine and PET. J Nucl Med 2007; 48:1436–41.CrossRefGoogle Scholar
21. Sun, H, Mangner, TJ, Collins, JM et al. Imaging DNA synthesis in vivo with 18FFMAU and PET. J Nucl Med 2005; 46(2):292–6.Google ScholarPubMed
22. 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.CrossRefGoogle ScholarPubMed
23. Jadvar, H, Yap, L-P, Park, R et al. [18F]-2’-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU) in prostate cancer: initial preclinical observations. Mol Imaging 2012; 11:426–32.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats No formats are currently available for this content.
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats No formats are currently available for this content.
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats No formats are currently available for this content.
×