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Neuro Oncol ; 16(1): 21-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24335554

RESUMO

BACKGROUND: Tumor irradiation blocks local angiogenesis, forcing any recurrent tumor to form new vessels from circulating cells. We have previously demonstrated that the post-irradiation recurrence of human glioblastomas in the brains of nude mice can be delayed or prevented by inhibiting circulating blood vessel-forming cells by blocking the interaction of CXCR4 with its ligand stromal cell-derived factor (SDF)-1 (CXCL12). In the present study we test this strategy by directly neutralizing SDF-1 in a clinically relevant model using autochthonous brain tumors in immune competent hosts. METHODS: We used NOX-A12, an l-enantiomeric RNA oligonucleotide that binds and inhibits SDF-1 with high affinity. We tested the effect of this inhibitor on the response to irradiation of brain tumors in rat induced by n-ethyl-N-nitrosourea. RESULTS: Rats treated in utero with N-ethyl-N-nitrosourea began to die of brain tumors from approximately 120 days of age. We delivered a single dose of whole brain irradiation (20 Gy) on day 115 of age, began treatment with NOX-A12 immediately following irradiation, and continued with either 5 or 20 mg/kg for 4 or 8 weeks, doses and times equivalent to well-tolerated human exposures. We found a marked prolongation of rat life span that was dependent on both drug dose and duration of treatment. In addition we treated tumors only when they were visible by MRI and demonstrated complete regression of the tumors that was not achieved by irradiation alone or with the addition of temozolomide. CONCLUSIONS: Inhibition of SDF-1 following tumor irradiation is a powerful way of improving tumor response of glioblastoma multiforme.


Assuntos
Neoplasias Encefálicas/prevenção & controle , Quimiocina CXCL12/antagonistas & inibidores , Recidiva Local de Neoplasia/prevenção & controle , Oligonucleotídeos Antissenso/farmacologia , Terapia por Raios X , Alquilantes/toxicidade , Animais , Neoplasias Encefálicas/induzido quimicamente , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Células Cultivadas , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Etilnitrosoureia/toxicidade , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Humanos , Imageamento por Ressonância Magnética , Camundongos , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/mortalidade , Ratos , Ratos Sprague-Dawley , Receptores CXCR/antagonistas & inibidores , Receptores CXCR/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Taxa de Sobrevida
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