Abstract |
The antivascular function of the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib combined with paclitaxel has been demonstrated by invasive immunohistochemistry. The purpose of this study was to 1) noninvasively monitor the response to anti-PDGFR treatment, and 2) understand the underlying mechanism of this response. Thus, response to treatment was studied in a prostate cancer bone metastasis model using macromolecular ( biotin- bovine serum albumin [BSA]-Gd- diethylene triamine pentaacetic acid [GdDTPA]) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Human prostate cancer (PC-3MM2) bone metastases that caused osteolysis and grew in neighboring muscle showed a high blood-volume fraction (fBV) and vascular permeability (PS) at the tumor periphery compared to muscle tissue and intraosseous tumor. Imatinib alone or with paclitaxel significantly reduced PS by 35% (one-tailed paired t-test, P = 0.045) and 40% (P = 0.0003), respectively, whereas paclitaxel alone or no treatment had no effect. Based on changes in PS, we hypothesized that imatinib interferes with the signaling pathway of vascular endothelial growth factor ( VEGF). This mechanism was verified by immunohistochemistry. It demonstrated reduced activation of both PDGFR-beta and VEGF receptor 2 (VEGFR2) in imatinib-treated mice. Our study therefore demonstrates that macromolecular DCE-MRI can be used to detect early vascular effects associated with response to therapy targeted to PDGFR, and provides insight into the role played by VEGF in anti-PDGFR therapy.
|
Authors | Hagit Dafni, Sun-Jin Kim, James A Bankson, Madhuri Sankaranarayanapillai, Sabrina M Ronen |
Journal | Magnetic resonance in medicine
(Magn Reson Med)
Vol. 60
Issue 4
Pg. 822-33
(Oct 2008)
ISSN: 1522-2594 [Electronic] United States |
PMID | 18816866
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
|
Copyright | (c) 2008 Wiley-Liss, Inc. |
Chemical References |
- Contrast Media
- Receptor, Platelet-Derived Growth Factor beta
- Receptors, Vascular Endothelial Growth Factor
- Gadolinium DTPA
|
Topics |
- Animals
- Bone Neoplasms
(diagnosis, drug therapy, secondary)
- Capillary Permeability
(drug effects)
- Cell Line, Tumor
- Contrast Media
- Down-Regulation
(drug effects)
- Gadolinium DTPA
- Magnetic Resonance Imaging
(methods)
- Male
- Mice
- Mice, Nude
- Prostatic Neoplasms
(diagnosis, drug therapy)
- Receptor, Platelet-Derived Growth Factor beta
(therapeutic use)
- Receptors, Vascular Endothelial Growth Factor
(metabolism)
- Treatment Outcome
|