semaxinib and Neuroblastoma

Malignant neuroblastomas are solid tumors in children. Available therapeutic agents are not highly effective for treatment of malignant neuroblastomas. Therefore, new treatment strategies are urgently needed. We tested the efficacy of combination of SU5416 (SU), an inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR-2), and (-)-epigallocatechin-3-gallate (EGCG), a polyphenolic compound from green tea, for controlling growth of human malignant neuroblastoma SH-SY5Y and SK-N-BE2 cells. Combination of 20 μM SU and 50 μM EGCG synergistically inhibited cell survival, suppressed expression of VEGFR-2, inhibited cell migration, caused cell cycle arrest, and induced apoptosis. Combination of SU and EGCG effectively blocked angiogenic and survival pathways and modulated expression of cell cycle regulators. Apoptosis was induced by down regulation of Bcl-2, activation of caspase-3, and cleavage of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). Taken together, this combination of drugs can be a promising therapeutic strategy for controlling the growth of human malignant neuroblastoma cells.

Topics: Angiogenesis Inhibitors; Anticarcinogenic Agents; Apoptosis; Catechin; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Survival; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; E2F1 Transcription Factor; Humans; In Situ Nick-End Labeling; Indoles; Neovascularization, Pathologic; Neuroblastoma; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Retinoblastoma Protein; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

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.

Topics: Angiogenesis Inhibitors; Animals; Cell Division; Cell Hypoxia; Combined Modality Therapy; Endothelium, Vascular; Gene Expression Regulation, Neoplastic; Humans; Hydrolases; Indoles; Mice; Mice, Nude; Neuroblastoma; Protein-Tyrosine Kinases; Pyrroles; Tumor Cells, Cultured; Whole-Body Irradiation; Xenograft Model Antitumor Assays

Vascular endothelial growth factor A (VEGF-A) and its receptor tyrosine kinases located on endothelial cells seem to play an important role in the multistep pathway of angiogenesis. SU5416 is a small molecule which inhibits angiogenesis by acting as an inhibitor of VEGF receptor-2 tyrosine kinase. We have developed a reproducible murine model for neuroblastoma, a childhood cancer, based on s.c. xenotransplantation of SH-SY5Y neuroblastoma cells. We found that SH-SY5Y cells expressed VEGF-A on both the mRNA and protein levels, that plasma concentrations of VEGF-A were significantly elevated in animals with neuroblastoma with a volume > 1.4 ml, and that there was a correlation between VEGF-A levels in plasma and tumor size in untreated tumor-bearing animals. Treatment with SU5416 reduced the growth of neuroblastoma tumors by 65% without apparent toxicity. SU5416 treatment also suppressed tumor angiogenesis, despite an increase in plasma VEGF-A levels per ml tumor volume during therapy. Our experimental data suggest that the angiogenesis inhibitor SU5416 may be beneficial in the treatment of solid tumors of childhood such as neuroblastoma.

Topics: Angiogenesis Inhibitors; Animals; Cell Division; Endothelial Growth Factors; Female; Humans; Indoles; Male; Mice; Mice, Nude; Neoplasms, Experimental; Neuroblastoma; Protein-Tyrosine Kinases; Pyrroles; Transplantation, Heterologous; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

CHS 828 is a new chemotherapeutic drug, a pyridyl cyanoguanidine. CHS 828 has low toxicity and lacks known patterns of multidrug resistance. Here we report that oral, daily treatment with CHS 828 reduced the growth of SH-SY5Y human neuroblastoma tumors in male NMRI nu/nu mice by 82% without apparent toxicity. CHS 828 induced complete tumor regression for at least 5 weeks in four of nine animals (44%). Combination therapy with CHS 828 and the antiangiogenic drugs TNP-470 or SU5416 decreased neuroblastoma growth by a further 10 and 3%, respectively. Combination therapy induced tumor regression at d 4 with CHS plus TNP and d 6 with CHS plus SU5416, compared with d 14 with CHS 828 alone (p < 0.05), and complete tumor regression was seen in nine of 19 animals (47%). Combination treatment of CHS 828 and TNP-470 decreased the total viable tumor volume by 71% compared with treatment with CHS 828 alone. Our findings support CHS 828 as a promising new drug in treatment of childhood cancers. Furthermore, they imply efficiency of daily administration of nontoxic doses of chemotherapy, and a possible additive effect when chemotherapy is combined with angiogenesis inhibitors.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Division; Cyanides; Cyclohexanes; Guanidines; Humans; Indoles; Male; Mice; Mice, Nude; Neovascularization, Pathologic; Neuroblastoma; O-(Chloroacetylcarbamoyl)fumagillol; Pyrroles; Remission Induction; Sesquiterpenes; Tumor Cells, Cultured; Xenograft Model Antitumor Assays