Arginine deiminase and other antiangiogenic agents inhibit unfavorable neuroblastoma growth: potentiation by irradiation.
In spite of aggressive therapy, children suffering from neuroblastoma have a poor prognosis. Therapeutic failure is most often observed in neuroblastomas with unfavorable features, including amplification/over-expression of the N-myc oncogene, rapid growth, effective angiogenesis and/or the tendency to metastasize. Here, we have used cultured human neuroblastoma cells with such features and we have examined whether antiangiogenic agents alone or in combination with tumor irradiation inhibit their angiogenesis and growth in vivo. We report that antiangiogenic agents (arginine deiminase, SU5416 and DC101) inhibit in vivo growth of neuroblastomas with unfavorable properties and that these effects are potentiated by simultaneous irradiation. Combination of either agent with irradiation leads to a reduction in the absolute number of tumor vessels and of perfused tumor vessels. Combination of arginine deiminase or DC101 with irradiation does not increase tumor hypoxia. Our data demonstrate for the first time that arginine deiminase suppresses the growth of unfavorable experimental neuroblastomas and that this effect is potentiated by irradiation. We suggest that antiangiogenesis alone or in combination with established therapeutic regimen may improve the outcome of unfavorable neuroblastomas in a clinical setting.
Gong
Hong
H
Department of Hematology, Oncology and Endocrinology, Children's Hospital, University of Essen, Essen, Germany.
Pöttgen
Christoph
C
Stüben
Georg
G
Havers
Werner
W
Stuschke
Martin
M
Schweigerer
Lothar
L
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D015687:Cell Hypoxia; D003131:Combined Modality Therapy; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006867:Hydrolases / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014916:Whole-Body Irradiation; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases; D006867:Hydrolases; C019723:arginine deiminase