title: Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats.
abstract: 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.
authors: Corresponding author: J. Martin Brown, PhD, Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, A246, 1050A Arastradero Rd, Palo Alto, CA 94304-1334. mbrown@stanford.edu.
authors: Shie-Chau
authors: SC
authors: Liu
authors: Reem
authors: R
authors: Alomran
authors: Sophia B
authors: SB
authors: Chernikova
authors: Fred
authors: F
authors: Lartey
authors: Jason
authors: J
authors: Stafford
authors: Taichang
authors: T
authors: Jang
authors: Milton
authors: M
authors: Merchant
authors: Dirk
authors: D
authors: Zboralski
authors: Stefan
authors: S
authors: Zöllner
authors: Anna
authors: A
authors: Kruschinski
authors: Sven
authors: S
authors: Klussmann
authors: Lawrence
authors: L
authors: Recht
authors: J Martin
authors: JM
authors: Brown
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D001932:Brain Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005038:Ethylnitrosourea / Q000633:toxicity; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054387:Receptors, CXCR / Q000037:antagonists & inhibitors / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015996:Survival Rate; D014964:X-Ray Therapy
chemical_list: C501898:Ackr3 protein, rat; D000477:Alkylating Agents; C515255:CXCL12 protein, human; C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D016376:Oligonucleotides, Antisense; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D005038:Ethylnitrosourea
keywords: CXCL12; CXCR4; CXCR7; ENU-induced tumors; NOX-A12; SDF-1; angiogenesis; glioblastoma; irradiation; vasculogenesis