Evaluation of arginine deiminase treatment in melanoma xenografts using (18)F-FLT PET.

Abstract

PURPOSE:

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

• Authors: Lars Stelter, Simon Fuchs, Achim A Jungbluth, Gerd Ritter, Valerie A Longo, Pat Zanzonico, Nathanael Raschzok, Igor M Sauer, John S Bomalaski, Steven M Larson
• Journal: Molecular imaging and biology (Mol Imaging Biol) Vol. 15 Issue 6 Pg. 768-75 (Dec 2013) ISSN: 1860-2002 [Electronic] United States
• PMID: 23722880 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dideoxynucleosides
• Ki-67 Antigen
• Tumor Suppressor Protein p53
• Thymidine Kinase
• thymidine kinase 1
• Hydrolases
• arginine deiminase
• alovudine

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Dideoxynucleosides (chemistry, pharmacokinetics)
• Hydrolases (pharmacology, therapeutic use)
• Immunohistochemistry
• Ki-67 Antigen (metabolism)
• Melanoma (drug therapy, pathology)
• Mice
• Signal Transduction (drug effects)
• Thymidine Kinase (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays