title: Cilengitide response in ultra-low passage glioblastoma cell lines: relation to molecular markers.
abstract: OBJECTIVE
  In glioblastoma multiforme (GBM), a tumor still characterized by dismal prognosis, recent research focuses on novel-targeted compounds, in addition to standard temozolomide (TMZ) chemotherapy. One of these emerging compounds is cilengitide (CGT), which by binding to integrins (i.e., αvβ3 and αvβ5) may inhibit angiogenesis and also is directly cytotoxic to tumor cells by interfering with intracellular signaling pathways.
  
  
  METHODS
  A total of ten patient-derived ultra-low passage GBM cell lines were treated with increasing doses of CGT, TMZ, and a combination of both substances. Inhibitory concentrations of 50% (IC₅₀) were determined for the single agents and as a combination. Cell lines were stratified according to MGMT promoter methylation. The expression of relevant integrins was assessed by flow cytometry.
  
  
  RESULTS
  In monotherapy, all GBM cell lines showed higher sensitivity to CGT than to TMZ, as determined by IC₅₀ values in relation to clinically relevant patient plasma levels. MGMT promoter methylation correlated with a significantly higher TMZ response, but tended to be associated with a lower CGT response. Response to CGT was not correlated with cell surface integrin expression as measured by flow cytometry. Finally, addition of CGT to TMZ enhanced growth inhibition, but only in those cell lines with a methylated MGMT promoter.
  
  
  CONCLUSIONS
  As suggested by this analysis, patients with MGMT promoter-methylated GBM may benefit from addition of CGT to the standard TMZ treatment, while patients with MGMT promoter-unmethylated GBM may better respond to CGT monotherapy.
authors.affiliation: University Children's Hospital, University Medicine, Ernst-Heydemann-Straße 8, 18057 Rostock, Germany. christina.mullins@uni-rostock.de
authors.forename: Christina S
authors.initials: CS
authors.lastname: Mullins
authors.forename: Julia
authors.initials: J
authors.lastname: Schubert
authors.forename: Björn
authors.initials: B
authors.lastname: Schneider
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebacher
authors.forename: Carl F
authors.initials: CF
authors.lastname: Classen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D002469:Cell Separation / Q000379:methods; D019175:DNA Methylation / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005434:Flow Cytometry; D005909:Glioblastoma / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D012910:Snake Venoms / Q000494:pharmacology*; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D012910:Snake Venoms; D025521:Tumor Suppressor Proteins; C422910:Cilengitide; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide