Macromolecular DCE-MRI detects reduced vascular permeability in aprostate cancer bone metastasis model following anti-PDGFR therapy indicating adrop in VEGFR activation

摘要

The anti-vascular function of platelet-derived growth factor receptor (PDGFR) inhibitor imatinib combined with paclitaxel has been demonstrated by invasive immunohistochemistry. The purpose of this study was 1. to noninvasively monitor the response to anti-PDGFR treatment and 2. to understand the underlying mechanism of this response. Thus, response to treatment was studied in a prostate cancer bone metastasis model using macromolecular (biotin-BSA-GdDTPA) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). PC-3MM2 bone metastases that caused osteolysis and grew in neighboring muscle showed 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-β and VEGFR2 in imatinib-treated mice. Our study therefore demonstrates thatmacromolecular DCE-MRI can be used to detect early vascular effects associatedwith response to therapy targeted to PDGFR and provides insight into the roleplayed by VEGF in anti-PDGFR therapy.