Novel mechanistic insights into arginine deiminase pharmacology suggest (18)F-FDG is not suitable to evaluate clinical response in melanoma Journal Article


Authors: Stelter, L.; Evans, M. J.; Jungbluth, A. A.; Zanzonico, P.; Ritter, G.; Ku, T.; Rosenfeld, E.; Bomalaski, J. S.; Old, L.; Larson, S. M.
Article Title: Novel mechanistic insights into arginine deiminase pharmacology suggest (18)F-FDG is not suitable to evaluate clinical response in melanoma
Abstract: Because of deficiencies in L-arginine biosynthesis, some cancers are susceptible to therapeutic intervention with arginine deiminase (ADI), an enzyme responsible for consuming the dietary supply of L-arginine to deprive the disease of an essential nutrient. ADI is currently being evaluated in several clinical trials, and fully realizing the drug's potential will depend on invoking the appropriate metrics to judge clinical response. Without a clear biologic mandate, PET/CT with 18F-FDG is currently used to monitor patients treated with ADI. However, it is unclear if it can be expected that 18F-FDG responses will indicate (or predict) clinical benefit. Methods: 18F-FDG responses to ADI therapy were studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was also studied, with a particular emphasis on biologic pathways known to regulate 18F-FDG avidity. Results: Although proliferation of SK-MEL 28 was potently inhibited by ADI treatment in vitro and in vivo, no clear declines in 18F-FDG uptake were observed. Further investigation showed that ADI treatment induces the posttranslational degradation of phosphatase and tensin homolog and the activation of the PI3K signaling pathway, an event known to enhance glycolysis and 18F-FDG avidity. A more thorough mechanistic study showed that ADI triggered a complex mechanism of cell death, involving apoptosis via poly (ADP-ribose) polymerase cleavage - independent of caspase 3. Conclusion: These findings suggest that some unexpected pharmacologic properties of ADI preclude using 18F-FDG to evaluate clinical response in melanoma and, more generally, argue for further studies to explore the use of PET tracers that target apoptotic pathway activation or cell death. Copyright © 2012 by the Society of Nuclear Medicine, Inc.
Keywords: signal transduction; controlled study; nonhuman; positron emission tomography; binding affinity; cell proliferation; animal cell; mouse; animal tissue; cell death; melanoma; apoptosis; protein degradation; animal experiment; animal model; in vivo study; caspase 3; antineoplastic activity; enzyme activation; in vitro study; molecular imaging; protein processing; biological activity; fluorodeoxyglucose f 18; clinical evaluation; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; drug sensitivity; glycolysis; protein cleavage; pi3k; 18f-fdg; isotope tracing; arginine deiminase; isotope analysis
Journal Title: Journal of Nuclear Medicine
Volume: 53
Issue: 2
ISSN: 0161-5505
Publisher: Society of Nuclear Medicine  
Date Published: 2012-02-01
Start Page: 281
End Page: 286
Language: English
DOI: 10.2967/jnumed.111.092973
PROVIDER: scopus
PUBMED: 22228793
DOI/URL:
Notes: --- - "Export Date: 1 March 2012" - "CODEN: JNMEA" - "Source: Scopus"
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MSK Authors
  1. Pat B Zanzonico
    359 Zanzonico
  2. Michael John Evans
    22 Evans
  3. Achim Jungbluth
    459 Jungbluth
  4. Gerd Ritter
    166 Ritter
  5. Steven M Larson
    960 Larson
  6. Lloyd J Old
    593 Old
  7. Thomas Ku
    12 Ku