title: 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.affiliation: 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.
authors.forename: Ji Yuan
authors.initials: JY
authors.lastname: Wu
authors.forename: David J
authors.initials: DJ
authors.lastname: Yang
authors.forename: Laura S
authors.initials: LS
authors.lastname: Angelo
authors.forename: Saady
authors.initials: S
authors.lastname: Kohanim
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: 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
chemical_list: 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