Molecular imaging of Bcr-Abl phosphokinase in a xenograft model.

Abstract

The purpose of this study was to determine whether the Bcr-Abl tyrosine kinase can be assessed by gamma-imaging using an 111In-labeled anti-phosphotyrosine (APT) antibody, and if the response to treatment with imatinib could be detected using this imaging technique. APT antibody was labeled with 111In using ethylenedicysteine (EC) as a chelator. To determine if 111In-EC-APT could assess a nonreceptor tyrosine kinase, xenografts of the human chronic myelogenous leukemia cell line K562 were used. gamma-Scintigraphy of the tumor-bearing mice, before and after imatinib treatment, was obtained 1, 24, and 48 h after they were given 111In-EC-APT (100 microCi/mouse i.v.). 111In-EC-APT is preferentially taken up by Bcr-Abl-bearing tumor cells when compared with 111In-EC-BSA or 111In-EC-IgG1 controls and comparable with the level of uptake of 111In-EC-Bcr-Abl. Imatinib treatment resulted in decreased expression of phospho-Bcr-Abl by Western blot analysis, which correlated with early (4 days after starting imatinib) kinase down-regulation as assessed by imaging using 111In-EC-APT. The optimal time to imaging was 24 and 48 h after injection of 111In-EC-APT. Although tumor regression was insignificant on day 4 after starting imatinib treatment, it was marked by day 14. 111In-EC-APT can assess intracellular phosphokinase activity, and down-regulation of phosphokinase activity predates tumor regression. This technique may therefore be useful in the clinic to detect the presence of phosphokinase activity and for early prediction of response.

• Authors: Ji Yuan Wu, David J Yang, Laura S Angelo, Saady Kohanim, Razelle Kurzrock
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 3 Pg. 703-10 (Mar 2009) ISSN: 1535-7163 [Print] United States
• PMID: 19258427 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies
• Benzamides
• Indium Radioisotopes
• Piperazines
• Pyrimidines
• ethylene dicysteine
• Phosphotyrosine
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl
• Cysteine

Topics

• Animals
• Antibodies
• Benzamides
• Cysteine (analogs & derivatives, pharmacokinetics)
• Female
• Fusion Proteins, bcr-abl (metabolism)
• Humans
• Imatinib Mesylate
• Indium Radioisotopes (pharmacokinetics)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (diagnostic imaging, drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Phosphotyrosine (immunology, pharmacokinetics)
• Piperazines (therapeutic use)
• Protein-Tyrosine Kinases (metabolism)
• Pyrimidines (therapeutic use)
• Radioimmunodetection (methods)
• Tumor Burden
• Xenograft Model Antitumor Assays