RT Journal Article
SR Electronic
T1 Combined Therapeutic Effects of Vinblastine and Rapamycin on Human Neuroblastoma Growth, Apoptosis, and Angiogenesis
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 3977
OP 3988
DO 10.1158/1078-0432.CCR-06-2757
VO 13
IS 13
A1 Marimpietri, Danilo
A1 Brignole, Chiara
A1 Nico, Beatrice
A1 Pastorino, Fabio
A1 Pezzolo, Annalisa
A1 Piccardi, Federica
A1 Cilli, Michele
A1 Di Paolo, Daniela
A1 Pagnan, Gabriella
A1 Longo, Luca
A1 Perri, Patrizia
A1 Ribatti, Domenico
A1 Ponzoni, Mirco
YR 2007
UL http://clincancerres.aacrjournals.org/content/13/13/3977.abstract
AB Purpose: Vinblastine and rapamycin displayed synergistic inhibition of human neuroblastoma-related angiogenesis. Here, we studied the antitumor activity of vinblastine and rapamycin against human neuroblastoma. Experimental Design: Cell proliferation, cell cycle progression, and apoptosis were evaluated by measuring 3H-thymidine incorporation, bromodeoxyuridine uptake, and phosphatidylserine exposure, respectively. The in vivo sensitivity of neuroblastoma cells to vinblastine and rapamycin was determined in orthotopic neuroblastoma-engrafted mice. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. Results: Each compound alone was able to induce a dose-dependent significant inhibition of cell proliferation, with a dramatically enhanced antiproliferative effect for the drugs used in combination. A marked G2-M cell cycle arrest with a nearly complete depletion of S phase was associated. The combined treatment triggered an increased apoptosis compared with either drug tested alone. A significant inhibition of tumor growth and microvessel area was obtained in neuroblastoma-bearing mice when treated with vinblastine or rapamycin alone, and a more dramatic effect with the combined treatment, compared with control mice. The therapeutic effectiveness, expressed as increased life span, was statistically improved by the combined therapy, compared with mice treated with either drug tested separately. Histologic evaluation of primary tumors showed that the combined treatment inhibited proliferation and angiogenesis and induced apoptosis. Combined treatment of neuroblastoma cells and neuroblastoma-bearing mice with vinblastine and rapamycin induced the down-modulation of both vascular endothelial growth factor production and vascular endothelial growth factor receptor 2 expression. In the chorioallantoic membrane assay, angiogenesis induced by human neuroblastoma biopsy specimens was significantly inhibited by vinblastine and rapamycin. Conclusions: These results may be relevant to design new therapeutic strategies against neuroblastoma.