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Combined Therapeutic Effects of Vinblastine and Rapamycin on Human Neuroblastoma Growth, Apoptosis, and Angiogenesis

Authors' Affiliations: ¹ Laboratory of Oncology, G.Gaslini Children's Hospital; ² Laboratory of Neuroblastoma Research and ³ Animal Research Facility, Italian Neuroblastoma Foundation c/o National Institute for Cancer Research, Genoa, Italy; and ⁴ Department of Human Anatomy and Histology, University of Bari, Bari, Italy

Requests for reprints: Mirco Ponzoni, Differentiation Therapy Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, Largo G. Gaslini 5, 16147 Genoa, Italy. Phone: 39-010-5636342; Fax: 39-010-3779820; E-mail: mircoponzoni{at}ospedale-gaslini.ge.it.

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.