Combination of anti-VEGF therapy and temozolomide in two experimental human glioma models

Rachel Grossman, Harry Brastianos, Jaishri O. Blakeley, Antonella Mangraviti, Bachchu Lal, Patti Zadnik, Lee Hwang, Robert T. Wicks, Rory C. Goodwin, Henry Brem, Betty Tyler

Research output: Contribution to journalArticlepeer-review

Abstract

Anti-angiogenic agents, such as bevacizumab (BEV), can induce normalization of the blood brain barrier, which may influence the penetration and activity of a co-administered cytotoxic drug. However, it is unknown whether this effect is associated with a benefit in overall survival. This study employed intracranial human glioma models to evaluate the effect of BEV alone and in combination with temozolomide (TMZ) and/or radiation therapy (XRT) on overall survival. One hundred eight male athymic rats were intracranially injected with either U251 or U87 human glioma. Ten or eleven days after tumor inoculation, animals bearing U251 and U87, respectively, were treated with: TMZ alone (50 mg/kg for 5 consecutive days, P.O.), BEV alone (15 mg/kg, I.V.), a combination of TMZ and BEV, or a combination of TMZ, BEV, and a single fraction of XRT (20 Gy). Controls received no treatment. The U87 experiment was repeated and the relationship between survival and the extent of anti-angiogenesis via anti-laminin antibodies for the detection of blood vessels was assessed. In both U87 glioma experiments, all of the treatment groups had a statistically significant increase in survival as compared to the control groups. Also, for both U87 experiments the combination groups of TMZ and BEV had significantly better survival when compared to either treatment administered alone, with 75 % of animals demonstrating long-term survival (LTS) (defined as animals alive 120 days after tumor implantation) in one experiment and 25 % LTS in the repeat experiment. In the U251 glioma experiment, all treated groups (except BEV alone) had significantly improved survival as compared to controls with minimal statistical variance among groups. The percent vessel area was lowest in the group of animals treated with BEV alone. The addition of BEV to TMZ and/or XRT had variable effect on prolonging survival in the two human glioma models tested with reduced tumor vascularity in groups treated with BEV. These results indicate that BEV has anti-angiogenic activity and does not seem to hinder the effect of TMZ.

Original languageEnglish (US)
Pages (from-to)59-65
Number of pages7
JournalJournal of neuro-oncology
Volume116
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • Angiogenesis
  • Bevacizumab
  • Brain tumor
  • Glioblastoma
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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