title: Imatinib mesylate enhances therapeutic effects of gemcitabine in human malignant mesothelioma xenografts.
abstract: OBJECTIVE
  Platelet-derived growth factor receptor beta (PDGFRbeta), frequently activated in malignant mesothelioma, is a promising cancer therapeutic target. Imatinib mesylate (STI571; Glivec) is a selective inhibitor of tyrosine kinases as bcr-abl, c-kit, c-fms, and PDGFRbeta and enhances tumor drug uptake by reducing the interstitial fluid pressure. We previously showed that imatinib mesylate synergizes with gemcitabine and pemetrexed in PDGFRbeta-positive mesothelioma cells. Here, we aimed at investigating these combined treatments in a novel mesothelioma model.
  
  
  METHODS
  REN mesothelioma cells, infected with a lentiviral vector carrying the luciferase gene, were injected in the peritoneum of severe combined immunodeficient mice. This model allowed imaging of live animals treated with pemetrexed or gemcitabine chemotherapeutics, or with imatinib mesylate alone, as well as with a combination of gemcitabine and imatinib mesylate.
  
  
  RESULTS
  We show here that, consistent with our previous in vitro studies, gemcitabine inhibited tumor growth, whereas pemetrexed was ineffective, even at the highest dosage tested. Compared with monotreatment, the combination of gemcitabine with imatinib mesylate led to a further tumor growth inhibition and improved mice survival, by a decrease rate of tumor cell proliferation and an increase in number of apoptotic tumor cells.
  
  
  CONCLUSIONS
  Imatinib mesylate enhances the therapeutic response to gemcitabine, in accordance with our previous in vitro data. These in vivo results validate imatinib mesylate and gemcitabine as a combination treatment of malignant mesothelioma, also in view of its known positive effects on tumor drug uptake. These evidences provide the rationale for the currently ongoing clinical trials.
authors.affiliation: Department of Chemical, Food, Pharmaceutical and Pharmacological Sciences and Drug and Food Biotechnology Center, University of Piemonte Orientale A Avogadro, Novara, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Bertino
authors.forename: Federica
authors.initials: F
authors.lastname: Piccardi
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.forename: Roberto
authors.initials: R
authors.lastname: Favoni
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.forename: Luciano
authors.initials: L
authors.lastname: Mutti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaudino
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D003841:Deoxycytidine; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D000093542:Gemcitabine