title: Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin.
abstract: BACKGROUND
  Although pemetrexed, a potent thymidylate synthase (TS) inhibitor, enhances the cytoytoxic effect of platinum compounds against malignant pleural mesothelioma (MPM), novel combinations with effective targeted therapies are warranted. To this end, the current study evaluates new targeted agents and their pharmacological interaction with carboplatin-pemetrexed in human MPM cell lines.
  
  
  METHODS
  We treated H2052, H2452, H28 and MSTO-211H cells with carboplatin, pemetrexed and targeted compounds (gefitinib, erlotinib, sorafenib, vandetanib, enzastaurin and ZM447439) and evaluated the modulation of pivotal pathways in drug activity and cancer cell proliferation.
  
  
  RESULTS
  Vandetanib emerged as the compound with the most potent cytotoxic activity, which interacted synergistically with carboplatin and pemetrexed. Drug combinations blocked Akt phosphorylation and increased apoptosis. Vandetanib significantly downregulated epidermal growth factor receptor (EGFR)/Erk/Akt phosphorylation as well as E2F-1 mRNA and TS mRNA/protein levels. Moreover, pemetrexed decreased Akt phosphorylation and expression of DNA repair genes. Finally, most MPM samples displayed detectable levels of EGFR and TS, the variability of which could be used for patients' stratification in future trials with vandetanib-pemetrexed-carboplatin combination.
  
  
  CONCLUSIONS
  Vandetanib markedly enhances pemetrexed-carboplatin activity against human MPM cells. Induction of apoptosis, modulation of EGFR/Akt/Erk phosphorylation and expression of key determinants for pemetrexed and carboplatin activity contribute to this synergistic interaction, and, together with the expression of these determinants in MPM samples, warrant further clinical investigation.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands. elisa.giovannetti@gmail.com
authors.forename: E
authors.initials: E
authors.lastname: Giovannetti
authors.forename: P A
authors.initials: PA
authors.lastname: Zucali
authors.forename: Y G
authors.initials: YG
authors.lastname: Assaraf
authors.forename: L G
authors.initials: LG
authors.lastname: Leon
authors.forename: K
authors.initials: K
authors.lastname: Smid
authors.forename: C
authors.initials: C
authors.lastname: Alecci
authors.forename: F
authors.initials: F
authors.lastname: Giancola
authors.forename: A
authors.initials: A
authors.lastname: Destro
authors.forename: L
authors.initials: L
authors.lastname: Gianoncelli
authors.forename: E
authors.initials: E
authors.lastname: Lorenzi
authors.forename: M
authors.initials: M
authors.lastname: Roncalli
authors.forename: A
authors.initials: A
authors.lastname: Santoro
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005971:Glutamates / Q000494:pharmacology / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D000068437:Pemetrexed; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D005971:Glutamates; D010880:Piperidines; D011799:Quinazolines; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin; D051057:Proto-Oncogene Proteins c-akt; C452423:vandetanib