Skip to main content
SpringerLink
Log in

Evaluation of Arginine Deiminase Treatment in Melanoma Xenografts Using 18F-FLT PET

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

This study aims to develop a molecular imaging strategy for response assessment of arginine deiminase (ADI) treatment in melanoma xenografts using 3′-[18F]fluoro-3′-deoxythymidine ([18F]-FLT) positron emission tomography (PET).

Procedures

F-FLT response to ADI therapy was studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was investigated, with a particular emphasis on biological pathways known to regulate 18F-FLT metabolism.

Results

Proliferation of SK-MEL-28 melanoma tumors was potently inhibited by ADI treatment. However, no metabolic response was observed in FLT PET, presumably based on the known ADI-induced degradation of PTEN, followed by instability of the tumor suppressor p53 and a relative overexpression of thymidine kinase 1, the enzyme mainly responsible for intracellular FLT processing.

Conclusion

The specific pharmacological properties of ADI preclude using 18F-FLT to evaluate clinical response in melanoma and argue for further studies to explore the use of other clinically applicable PET tracers in ADI treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Izzo F, Marra P, Beneduce G et al (2004) Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies. J Clin Oncol 22:1815–1822

    Article  PubMed  CAS  Google Scholar 

  2. Ascierto PA, Scala S, Castello G et al (2005) Pegylated arginine deiminase treatment of patients with metastatic melanoma: results from phase I and II studies. J Clin Oncol 23:7660–7668

    Article  PubMed  CAS  Google Scholar 

  3. Glazer ES, Piccirillo M, Albino V et al (2010) Phase II study of pegylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma. J Clin Oncol 28:2220–6

    Article  PubMed  CAS  Google Scholar 

  4. Feun LG, Marini A, Walker G et al (2012) Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase. Br J Cancer 106:1481–5

    Article  PubMed  CAS  Google Scholar 

  5. Dillon BJ, Prieto VG, Curley SA et al (2004) Incidence and distribution of argininosuccinate synthetase deficiency in human cancers. Cancer 100:826–33

    Article  PubMed  CAS  Google Scholar 

  6. Kim RH, Coates JM, Bowles TL et al (2009) Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. Cancer Res 69:700–8

    Article  PubMed  CAS  Google Scholar 

  7. Kelly MP, Junbluth AA, Wu BW et al (2012) Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase. Br J Cancer 106:324–32

    Article  PubMed  CAS  Google Scholar 

  8. Kobayashi E, Masuda M, Nakayama R et al (2010) Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma. Mol Cancer Ther 9:535–44

    Article  PubMed  CAS  Google Scholar 

  9. Larson SM, Schwartz LH (2006) 18F-FDG as a candidate for “qualified biomarker”: functional assessment of treatment response in oncology. J Nucl Med 47:901–3

    PubMed  CAS  Google Scholar 

  10. Stelter L, Evans MJ, Jungbluth AA et al (2012) Novel mechanistic insights into arginine deiminase pharmacology suggest 18F-FDG is not suitable to evaluate clinical response in melanoma. J Nucl Med 53:281–6

    Article  PubMed  CAS  Google Scholar 

  11. Ott PA, Carvajal RD, Pandit-Taskar N et al (2012) Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma. Invest New Drugs 31(2):425–34. doi:10.1007/s10637-012-9862-2

    Article  PubMed  Google Scholar 

  12. Rasey JS, Grierson JR, Wiens LW et al (2002) Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med 43:1210–17

    PubMed  CAS  Google Scholar 

  13. Been LB, Suurmeijer AJH, Cobben DCP et al (2004) [18-F]FLT-PET in oncology: current status and opportunities. Eur J Nucl Med Biol 31:1659–1672

    Article  Google Scholar 

  14. Liu W, Zhou Y, Reske SN, Shen C (2008) PTEN Mutation: many birds with one stone in tumorigenesis. anticancer Res 28:3613–3620

    PubMed  CAS  Google Scholar 

  15. Benz MR, Czernin J, Allen-Auerbach MS et al (2012) 3′-Deoxy-3′-[18F] fluorothymidine positron emission tomography for response assessment in soft tissue sarcoma. Cancer 118:3135–44

    Article  PubMed  Google Scholar 

  16. Savaraj N, You M, Wu C et al (2010) Arginine deprivation, autophagy, apoptosis (AAA) for the treatment of melanoma. Curr Mol Med 10:405–412

    Article  PubMed  CAS  Google Scholar 

  17. Syed N, Langer J, Janczar K et al (2013) Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma. Cell Death Dis 4:e458

    Article  PubMed  CAS  Google Scholar 

  18. Delage B, Luong P, Maharaj L et al (2012) Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis. Cell Death Dis 3:e342

    Article  PubMed  CAS  Google Scholar 

  19. You M, Savaraj N, Wangpaichitr M et al (2010) The combination of ADI-PEG20 and TRAIL effectively increases cell death in melanoma cell lines. Biochem Biophys Res Com 394:760–76

    Article  PubMed  CAS  Google Scholar 

  20. Lucignani G, Larson SM (2010) Doctor, what does my future hold? The prognostic value of FDG-PET in solid tumours. Eur J Nucl Med Mol Imaging 37:1032–8

    Article  PubMed  Google Scholar 

  21. Larson SM, Robbins R (2002) Positron emission tomography in thyroid cancer management. Semin Roentgenol 37:169–74

    Article  PubMed  Google Scholar 

  22. Lu SJ, Gnanasegaran G, Buscombe J, Navalkissoor S (2013) Single photon emission computed tomography/computed tomography in the evaluation of neurendocrine tumours: a review of the literature. Nucl Med Commun 34:98–107

    Article  PubMed  Google Scholar 

  23. Stelter L, Evans MJ, Junbluth AA et al (2013) Imaging of tumor vascularization using fluorescence molecular tomography to monitor arginine deiminase treatment in melanoma. Mol Imaging 12:67–73

    PubMed  CAS  Google Scholar 

  24. Szlosarek PW, Luong P, Phillips MM et al (2013) Metabolic response to pegylated arginine deiminase in mesothelioma with promoter methylation of argininosuccinate synthetase. J Clin Oncol 31:1–3

    Article  Google Scholar 

  25. Hoshikawa H, Nishiyama Y, Kishino T et al (2011) Comparison of FLT-PET and FDG-PET for visualization of head and neck squamous cell cancers. Mol Img Biol 13:172.7

    Google Scholar 

  26. Fatema CN, Zhao S, Zhao Y et al (2013) Monitoring tumor proliferation response to radiotherapy using (18)F-fluorothymidine in human head and neck cancer xenograft in comparison with Ki-67. Ann Nucl Med 27(4):355–62. doi:10.1007/s12149-013-0693-9

    Article  PubMed  CAS  Google Scholar 

  27. Sherley JL, Kelly TJ (1988) Regulation of human thymidine kinase during the cell cycle. J Biol Chem 263:8350–8358

    PubMed  CAS  Google Scholar 

  28. Wang H, He Q, Skog S, Eriksson S, Tribukait B (2001) Investigation on cell proliferation with a new antibody against thymidine kinase 1. Anal Cell Pathol 23:11–19

    PubMed  Google Scholar 

  29. De Saint-Hubert M, Brepoels L, Devos E et al (2012) Molecular imaging of therapy response with (18)F-FLT and (18)F-FDG following cyclophosphamide and mTOR inhibition. Am J Nucl Med Mol Img 1:110–121

    Google Scholar 

  30. Feun L, Savaraj N (2006) Pegylated arginine deiminase: a novel anticancer enzyme agent. Expert Opin Investig Drugs 15:815–822

    Article  PubMed  CAS  Google Scholar 

  31. Mayo LD, Dixon DB, Durden DL et al (2002) PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem 277:5484–9

    Article  PubMed  CAS  Google Scholar 

  32. Schwartz JL, Tamura Y, Jordan R et al (2004) Effect of p53 activation on cell growth, thymidine kinase-1 activity, and 3′-deoxy-3′fluorothymidine uptake. Nucl Med Biol 31:419–423

    Article  PubMed  CAS  Google Scholar 

  33. Freeman DJ, Li AG, Wei G et al (2003) PTEN tumor suppressor regulates p53 protein levels and activity through phostphatase-dependant and -independent mechanisms. Cancer Cell 3:117–30

    Article  PubMed  CAS  Google Scholar 

  34. Cui X, Witalison EE, Chumanevich AP et al (2013) The induction of microRNA-16 in colon cancer cells by protein arginine deiminase inhibition cause a p53-dependent cell cycle arrest. PLoS One 8:e53791

    Article  PubMed  CAS  Google Scholar 

  35. Paproski RJ, Wuest M, Jans HS et al (2010) Biodistribution and uptake of 3′deoxy-3′-fluorothymidine in ENT1-knockout mice and in an ENT1-knockdown tumor model. J Nucl Med 51:1447–55

    Article  PubMed  CAS  Google Scholar 

  36. Plotnik DA, McLaughlin LJ, Chan J et al (2011) The role of nucleoside/nucleotide transport and metabolism in the uptake and retention of 3′-fluoro-3′-deoxythymidine in human B-lymphoblast cells. Nucl Med Biol 38:979–86

    Article  PubMed  CAS  Google Scholar 

  37. Plotnik DA, McLaughlin LJ, Krohn KA, Schwartz JL (2012) The effects of 5-fluoruracil treatment on 3′-fluoro-3′deoxythymidine (FLT) transport and metabolism in proliferating and non-proliferating cultures of human tumor cells. Nucl Med Biol 39:970–976

    Article  PubMed  CAS  Google Scholar 

  38. Höglund J, Shirvan A, Antoni G et al (2011) 18F-ML-10, a PET tracer for apoptosis: first human study. J Nucl Med 52:720–5

    Article  PubMed  Google Scholar 

  39. Sobrio F, Médoc M, Martial L et al (2013) Automated radiosynthesis of [(18)F]ML-10, a PET radiotracer dedicated to apoptosis imaging, on a TRACERLab FX-FN module. Mol Imaging Biol 15:12–8

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. Marcus Kelly for his informative discussions and Megan Holz for her invaluable assistance. We also thank the staff of the Radiochemistry/Cyclotron Core at MSKCC. Technical services provided by the MSKCC Small-Animal Imaging Core Facility were supported in part by NIH grants R24 CA83084 and P30 CA08748. L.S. was supported by a grant (Ste 1837/1-1) of the Deutsche Forschungsgemeinschaft.

Conflict of Interest

J.S.B. is the Executive Vice President of Polaris Group that provided ADI-PEG 20 for this study. All other authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Radiology, Charité CVK–Universitätsmedizin Berlin, 13353, Berlin, Germany

    Lars Stelter & Simon Fuchs

  2. Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    Lars Stelter, Valerie A. Longo, Pat Zanzonico & Steven M. Larson

  3. Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    Achim A. Jungbluth, Gerd Ritter & Steven M. Larson

  4. Department of General, Visceral and Transplant Surgery, Experimental Surgery and Regenerative Medicine, Charité CVK–Universitätsmedizin Berlin, 13353, Berlin, Germany

    Nathanael Raschzok & Igor M. Sauer

  5. Polaris Group, San Diego, CA, 92121, USA

    John S. Bomalaski

  6. Program in Molecular Pharmacology and Chemistry, at Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    Steven M. Larson

Authors
  1. Lars Stelter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simon Fuchs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Achim A. Jungbluth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gerd Ritter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Valerie A. Longo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pat Zanzonico
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nathanael Raschzok
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Igor M. Sauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John S. Bomalaski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Steven M. Larson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lars Stelter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stelter, L., Fuchs, S., Jungbluth, A.A. et al. Evaluation of Arginine Deiminase Treatment in Melanoma Xenografts Using 18F-FLT PET. Mol Imaging Biol 15, 768–775 (2013). https://doi.org/10.1007/s11307-013-0655-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-013-0655-6

Key words

Search

Navigation