title: c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients.
abstract: BACKGROUND
  To study whether and how c-MYC expression determines response to radio- and chemotherapy in childhood medulloblastoma (MB).
  
  
  METHODS
  We used DAOY and UW228 human MB cells engineered to stably express different levels of c-MYC, and tested whether c-MYC expression has an effect on radio- and chemosensitivity using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay, clonogenic survival, apoptosis assays, cell cycle analysis, and western blot assessment. In an effort to validate our results, we analyzed c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor samples from well-documented patients with postoperative residual tumor and compared c-MYC mRNA expression with response to radio- and chemotherapy as examined by neuroradiological imaging.
  
  
  RESULTS
  In DAOY - and to a lesser extent in UW228 - cells expressing high levels of c-MYC, the cytotoxicity of cisplatin, and etoposide was significantly higher when compared with DAOY/UW228 cells expressing low levels of c-MYC. Irradiation- and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. The response of 62 of 66 residual tumors was evaluable and response to postoperative radio- (14 responders (CR, PR) vs. 5 non-responders (SD, PD)) or chemotherapy (23 CR/PR vs. 20 SD/PD) was assessed. c-MYC mRNA expression was similar in primary MB samples of responders and non-responders (Mann-Whitney U test, p = 0.50, ratio 0.49, 95% CI 0.008-30.0 and p = 0.67, ratio 1.8, 95% CI 0.14-23.5, respectively).
  
  
  CONCLUSIONS
  c-MYC sensitizes MB cells to some anti-cancer treatments in vitro. As we failed to show evidence for such an effect on postoperative residual tumors when analyzed by imaging, additional investigations in xenografts and larger MB cohorts may help to define the exact function of c-MYC in modulating response to treatment.
authors.affiliation: Neuro-Oncology Program, University Children's Hospital, Zurich, Switzerland. a.von-bueren@uke.de
authors.forename: André O
authors.initials: AO
authors.lastname: von Bueren
authors.forename: Christoph
authors.initials: C
authors.lastname: Oehler
authors.forename: Tarek
authors.initials: T
authors.lastname: Shalaby
authors.forename: Katja
authors.initials: K
authors.lastname: von Hoff
authors.forename: Martin
authors.initials: M
authors.lastname: Pruschy
authors.forename: Burkhardt
authors.initials: B
authors.lastname: Seifert
authors.forename: Nicolas U
authors.initials: NU
authors.lastname: Gerber
authors.forename: Monika
authors.initials: M
authors.lastname: Warmuth-Metz
authors.forename: Duncan
authors.initials: D
authors.lastname: Stearns
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Kortmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Rutkowski
authors.forename: Michael A
authors.initials: MA
authors.lastname: Grotzer
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D011379:Prognosis; D011836:Radiation Tolerance / Q000235:genetics* / Q000502:physiology; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D055815:Young Adult