Combination of metronomic cyclophosphamide and dietary intervention inhibits neuroblastoma growth in a CD1-nu mouse model
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Raphael Johannes Morscher1,4, Sepideh Aminzadeh-Gohari1, Cornelia Hauser-Kronberger2, René Günther Feichtinger1, Wolfgang Sperl3, Barbara Kofler1
1Laura Bassi Centre of Expertise-THERAPEP, Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria
2Department of Pathology, Paracelsus Medical University, 5020 Salzburg, Austria
3Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria
4Division of Medical Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria
Raphael Johannes Morscher, e-mail: firstname.lastname@example.org
Keywords: neuroblastoma, ketogenic diet, glucose, metronomic cyclophosphamide, anti-angiogenic
Received: September 15, 2015 Accepted: February 05, 2016 Published: March 05, 2016
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.
Methods and 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.
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