Molecular imaging of Bcr-Abl phosphokinase in a xenograft model.
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.
Wu
Ji Yuan
JY
Department of Investigational Cancer Therapeutics (Phase I Program), Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Unit 455, P.O. Box 301402, Houston, TX 77030, USA.
Yang
David J
DJ
Angelo
Laura S
LS
Kohanim
Saady
S
Kurzrock
Razelle
R
D000818:Animals; D000906:Antibodies; D001549:Benzamides; D003545:Cysteine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D019000:Phosphotyrosine / Q000276:immunology* / Q000493:pharmacokinetics; D010879:Piperazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D016719:Radioimmunodetection / Q000379:methods*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D001549:Benzamides; D007205:Indium Radioisotopes; D010879:Piperazines; D011743:Pyrimidines; C109063:ethylene dicysteine; D019000:Phosphotyrosine; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D003545:Cysteine