title: Early effects of imatinib mesylate on the expression of insulin-like growth factor binding protein-3 and positron emission tomography in patients with gastrointestinal stromal tumor.
abstract: BACKGROUND
  Imatinib has demonstrated marked clinical efficacy against gastrointestinal stromal tumor (GIST). Microarray technology, real-time polymerase chain reaction (PCR) validation, and fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging were used to study the early molecular effects of imatinib antitumor activity in GIST.
  
  
  METHODS
  After exposure of sensitive and resistant sarcoma cell lines to imatinib for 24 to 48 hours, the changes in gene expression were evaluated using a 1146 unique pathway array with Western blot validation. Real-time PCR was used to confirm changes in gene expression in human GIST samples (preimatinib biopsy and postimatinib surgical specimen after 3-7 days of therapy). FDG-PET was performed to correlate radiographic findings with the effects of imatinib on gene expression in GIST.
  
  
  RESULTS
  In all, 55 genes demonstrated a > or = 2-fold change after imatinib treatment of the GIST882 cells. Among these genes there was up-regulation of insulin-like growth factor binding protein-3 (IGFBP-3), a protein that modulates proliferation and apoptosis. Western blot analysis confirmed the increase of IGFBP-3 only in imatinib-sensitive GIST882 cells. Up to a 7-fold induction (49% mean increase; P = .08) of IGFBP-3 mRNA was found in tumor samples from patients with low residual FDG uptake, whereas there was an up to 12-fold reduction (-102% mean decrease; P = .03) in IGFBP-3 in those patients with high residual FDG uptake after imatinib therapy.
  
  
  CONCLUSIONS
  In the current study, imatinib appears to regulate numerous genes and specifically induces IGFBP-3 in GIST cells and tumor samples. IGFBP-3 levels also were found to be inversely correlated with residual FDG uptake in GIST patients early in imatinib therapy. These initial observations suggest that IGFBP-3 is an important early marker of antitumor activity of imatinib in GIST.
authors.affiliation: Department of Sarcoma Medical Oncology, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. jtrent@mdanderson.org
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trent
authors.forename: Latha
authors.initials: L
authors.lastname: Ramdas
authors.forename: Jheri
authors.initials: J
authors.lastname: Dupart
authors.forename: Kelly
authors.initials: K
authors.lastname: Hunt
authors.forename: Homer
authors.initials: H
authors.lastname: Macapinlac
authors.forename: Ellen
authors.initials: E
authors.lastname: Taylor
authors.forename: Limei
authors.initials: L
authors.lastname: Hu
authors.forename: August
authors.initials: A
authors.lastname: Salvado
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Raphael
authors.initials: R
authors.lastname: Pollock
authors.forename: Robert S
authors.initials: RS
authors.lastname: Benjamin
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides; D002470:Cell Survival; D046152:Gastrointestinal Stromal Tumors / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011743:Pyrimidines / Q000494:pharmacology*; D011859:Radiography; D012509:Sarcoma / Q000235:genetics; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate