title: TL-118 and gemcitabine drug combination display therapeutic efficacy in a MYCN amplified orthotopic neuroblastoma murine model--evaluation by MRI.
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.
authors.affiliation: The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel; MRI/MRS lab HBRC, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Chani
authors.initials: C
authors.lastname: Komar-Stossel
authors.affiliation: Pediatric Surgery, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Gross
authors.affiliation: The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel; MRI/MRS lab HBRC, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Elia
authors.initials: E
authors.lastname: Dery
authors.affiliation: The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel; MRI/MRS lab HBRC, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Corchia
authors.affiliation: Pathology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Karen
authors.initials: K
authors.lastname: Meir
authors.affiliation: Pediatric Hemato-Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Fried
authors.affiliation: The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel; MRI/MRS lab HBRC, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Rinat
authors.initials: R
authors.lastname: Abramovitch
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002927:Cimetidine / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004008:Diclofenac / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004357:Drug Synergism; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000071447:N-Myc Proto-Oncogene Protein; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D009447:Neuroblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012460:Sulfasalazine / Q000008:administration & dosage; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D004338:Drug Combinations; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C575718:TL-118; D003841:Deoxycytidine; D004008:Diclofenac; D012460:Sulfasalazine; D014212:Tretinoin; D002927:Cimetidine; D003520:Cyclophosphamide; D000093542:Gemcitabine