title: Targeting platelet-derived growth factor receptor on endothelial cells of multidrug-resistant prostate cancer.
abstract: BACKGROUND
  Inhibiting phosphorylation of platelet-derived growth factor receptor (PDGFR) by treatment with the PDGFR kinase inhibitor imatinib and the chemotherapeutic agent paclitaxel reduces the incidence and size of human prostate cancer bone lesions in nude mice. Because tumor cells and tumor-associated endothelial cells express activated PDGFR, the primary target for imatinib has been unclear.
  
  
  METHODS
  We selected multidrug-resistant human PC-3MM2 prostate cancer cells (termed PC-3MM2-MDR cells) by culturing them in increasing concentrations of paclitaxel. PC-3MM2-MDR cells were implanted into one tibia of 80 nude mice. Two weeks later, the mice were randomly assigned to receive distilled water (control group), paclitaxel, imatinib, or imatinib plus paclitaxel for 10 weeks (20 mice per group). Tumor incidence and weight, bone structure preservation and osteolysis, and the incidence of lymph node metastasis were determined. The phosphorylation status of PDGFR on tumor cells and tumor-associated endothelial cells and levels of apoptosis were examined with immunohistochemical analyses. Microvessel density was assessed as the number of cells expressing CD31/platelet endothelial cell adhesion molecule 1 (PECAM-1). All statistical tests were two-sided.
  
  
  RESULTS
  PC-3MM2-MDR cells were resistant to paclitaxel and imatinib in vitro. Treatment of implanted mice with imatinib plus paclitaxel led to statistically significant decreases in bone tumor incidence (control = 19 mice with tumors of 19 mice total; imatinib plus paclitaxel = four of 18 mice; P < .001), median tumor weight (control = 1.3 g, interquartile range [IQR] = 1.0-1.9; imatinib plus paclitaxel = 0.1 g, IQR = 0-0.3; P < .001), bone lysis, and the incidence of lymph node metastasis (control = 19 of 19 mice total; imatinib plus paclitaxel = three of 18 mice; P < .001). Treatment with imatinib alone had similar effects, and imatinib treatment also inhibited phosphorylation of PDGFR on tumor cells and tumor-associated endothelial cells and increased the level of apoptosis of endothelial cells, but not tumor cells. Treatment with imatinib and more so with imatinib and paclitaxel decreased mean vessel density (three CD31/PECAM-1-positive cells, 95% confidence interval [CI] = 0 to 9; and control group = 38 CD31/PECAM-1-positive cells, 95% CI = 17 to 59) (P < .001), which was followed by apoptosis of tumor cells.
  
  
  CONCLUSIONS
  Tumor-associated endothelial cells, rather than tumor cells themselves, appear to be the target for imatinib in prostate cancer bone metastasis.
authors.affiliation: Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.forename: Sertac
authors.initials: S
authors.lastname: Yazici
authors.forename: Joseph Erik
authors.initials: JE
authors.lastname: Busby
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.forename: Junqin
authors.initials: J
authors.lastname: He
authors.forename: Marva
authors.initials: M
authors.lastname: Maya
authors.forename: Christopher
authors.initials: C
authors.lastname: Logothetis
authors.forename: Paul
authors.initials: P
authors.lastname: Mathew
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.forename: Dominic
authors.initials: D
authors.lastname: Fan
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Fidler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000098:blood supply / Q000737:chemistry / Q000517:prevention & control* / Q000556:secondary*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008207:Lymphatic Metastasis / Q000517:prevention & control; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D011897:Random Allocation; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D017239:Paclitaxel