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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
Article first published online: 19 SEP 2006
Copyright © 2006 American Cancer Society
Volume 107, Issue 8, pages 1898–1908, 15 October 2006
How to Cite
Trent, J. C., Ramdas, L., Dupart, J., Hunt, K., Macapinlac, H., Taylor, E., Hu, L., Salvado, A., Abbruzzese, J. L., Pollock, R., Benjamin, R. S. and Zhang, W. (2006), 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. Cancer, 107: 1898–1908. doi: 10.1002/cncr.22214
- Issue published online: 3 OCT 2006
- Article first published online: 19 SEP 2006
- Manuscript Accepted: 13 JUL 2006
- Manuscript Revised: 25 MAY 2006
- Manuscript Received: 7 FEB 2006
- Physician-Scientist Award
- National Institutes of Health/National Cancer Institute (NIH/NCI). Grant Number: 1K23CA109060-01
- NIH/NCI. Grant Number: R01 CA098570
- Michael and Betty Kadoorie Foundation
- Goodwin Fund
- National cancer Institute Cancer Center. Grant Number: CA-16672
- gastrointestinal stromal tumor;
- gene expression;
- imatinib mesylate;
- insulin-like growth factor binding protein-3;
- positron emission tomography
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.
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.
In all, 55 genes demonstrated a ≥ 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.
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. Cancer 2006. © 2006 American Cancer Society.