title: Combination of metronomic cyclophosphamide and dietary intervention inhibits neuroblastoma growth in a CD1-nu mouse model.
abstract: BACKGROUND
  MYCN-amplification in high-grade Neuroblastoma (NB) tumors correlates with increased vascularization and therapy resistance. This study combines an anti-angiogenic approach with targeting NB metabolism for treatment.
  
  
  RESULTS
  Metronomic cyclophosphamide (MCP) monotherapy significantly inhibited NB growth and prolonged host survival. Growth inhibition was more pronounced in MYCN-amplified xenografts. Immunohistochemical evaluation of this subtype showed significant decrease in blood vessel density and intratumoral hemorrhage accompanied by blood vessel maturation and perivascular fibrosis. Up-regulation of VEGFA was not sufficient to compensate for the effects of the MCP regimen. Reduced Bcl-2 expression and increased caspase-3 cleavage were evident. In contrast non MYCN-amplified tumors developed resistance, which was accompanied by Bcl-2-up-regulation. Combining MCP with a ketogenic diet and/or calorie-restriction significantly enhanced the anti-tumor effect. Calorie-restricted ketogenic diet in combination with MCP resulted in tumor regression in all cases.
  
  
  CONCLUSIONS
  Our data show efficacy of combining an anti-angiogenic cyclophosphamide dosing regimen with dietary intervention in a preclinical NB model. These findings might open a new front in NB treatment.
authors.affiliation: Laura Bassi Centre of Expertise-THERAPEP, Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria.|Division of Medical Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Raphael Johannes
authors.initials: RJ
authors.lastname: Morscher
authors.affiliation: Laura Bassi Centre of Expertise-THERAPEP, Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Sepideh
authors.initials: S
authors.lastname: Aminzadeh-Gohari
authors.affiliation: Department of Pathology, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hauser-Kronberger
authors.affiliation: Laura Bassi Centre of Expertise-THERAPEP, Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: René Günther
authors.initials: RG
authors.lastname: Feichtinger
authors.affiliation: Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.affiliation: Laura Bassi Centre of Expertise-THERAPEP, Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kofler
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects*; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004035:Diet Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003520:Cyclophosphamide
keywords: anti-angiogenic; glucose; ketogenic diet; metronomic cyclophosphamide; neuroblastoma