Abstract
Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor with up to 50% of NB patients classified as having high-risk disease with poor long-term survival rates. The poor clinical outcome and aggressiveness of high-risk NB strongly correlates with enhanced angiogenesis, suggesting anti-angiogenic agents as attractive additions to the currently insufficient therapeutics. TL-118, a novel drug combination has been recently developed to inhibit tumor angiogenesis. In the current study, we used the SK-N-BE (2) cell line to generate orthotopic NB tumors in order to study the combinational therapeutic potential of TL-118 with either Gemcitabine (40 mg/kg; IP) or Retinoic acid (40 mg/kg; IP). We show that TL-118 treatment (n = 9) significantly inhibited tumor growth, increased cell apoptosis, reduced proliferation and extended mouse survival. Moreover, the reciprocal effect of TL-118 and Gemcitabine treatment (n = 10) demonstrated improved anti-tumor activity. The synergistic effect of these drugs in combination was more effective than either TL or Gemcitabine alone (n = 9), via significantly reduced cell proliferation (p<0.005), increased apoptosis (p<0.05) and significantly prolonged survival (2-fold; p<0.00001). To conclude, we demonstrate that the novel drug combination TL-118 has the ability to suppress the growth of an aggressive NB tumor. The promising results with TL-118 in this aggressive animal model may imply that this drug combination has therapeutic potential in the clinical setting.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cimetidine / administration & dosage
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Cyclophosphamide / administration & dosage
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Deoxycytidine / administration & dosage
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Deoxycytidine / analogs & derivatives
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Diclofenac / administration & dosage
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Drug Administration Schedule
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Drug Combinations
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Drug Synergism
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Gemcitabine
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Gene Amplification*
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Humans
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Immunohistochemistry
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Magnetic Resonance Imaging / methods*
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Male
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Mice, Inbred NOD
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Mice, SCID
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N-Myc Proto-Oncogene Protein
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / metabolism
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Neuroblastoma / blood supply
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Neuroblastoma / drug therapy*
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Neuroblastoma / genetics
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Nuclear Proteins / genetics*
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Oncogene Proteins / genetics*
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Sulfasalazine / administration & dosage
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Treatment Outcome
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Tretinoin / administration & dosage
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays*
Substances
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Drug Combinations
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MYCN protein, human
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N-Myc Proto-Oncogene Protein
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Nuclear Proteins
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Oncogene Proteins
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Platelet Endothelial Cell Adhesion Molecule-1
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TL-118
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Deoxycytidine
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Diclofenac
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Sulfasalazine
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Tretinoin
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Cimetidine
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Cyclophosphamide
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Gemcitabine
Grants and funding
This research was supported by a grant from the Israeli Cancer Association (20130099) and a financial support from Manferd and Sabine Landau (London). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.