Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines

  1. Lookup NU author(s)
  2. Dr Evan Mulligan
  3. Professor Nicola Curtin
  4. Professor Ruth Plummer
Author(s)Clarke MJ, Mulligan EA, Grogan PT, Mladek AC, Carlson BL, Schroeder MA, Curtin NJ, Lou Z, Decker PA, Wu W, Plummer ER, Sarkaria JN
Publication type Article
JournalMolecular Cancer Therapeutics
Year2009
Volume8
Issue2
Pages407-414
ISSN (print)1535-7163
ISSN (electronic)1538-8514
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Resistance to temozolomide and radiotherapy is a major problem for patients with glioblastoma but may be overcome using the poly(ADP-ribose) polymerase inhibitor ABT-888. Using two primary glioblastoma xenografts, the efficacy of ABT-888 combined with radiotherapy and/or temozolomide was evaluated. Treatment with ABT-888 combined with temozolomide resulted in significant survival prolongation (GBM12: 55.1%, P = 0.005; GBM22: 54.4%, P = 0.043). ABT-888 had no effect with radiotherapy alone but significantly enhanced survival in GBM12 when combined with concurrent radiotherapy/temozolomide. With multicycle therapy, ABT-888 further extended the survival benefit of temozolomide in the inherently sensitive GBM12 and GBM22 xenograft lines. However, after in vivo selection for temozolomide resistance, the derivative GBM12TMZ and GBM22TMZ lines were no longer sensitized by ABT-888 in combination with temozolomide, and a similar lack of efficacy was observed in two other temozolomide-resistant tumor lines. Thus, the sensitizing effects of ABT-888 were limited to tumor lines that have not been previously exposed to temozolomide, and these results suggest that patients with newly diagnosed glioblastoma may be more likely to respond to combined temozolomide/poly(ADP-ribose) polymerase inhibitor therapy than patients with recurrent disease.
PublisherAmerican Association for Cancer Research
URLhttp://dx.doi.org/10.1158/1535-7163.MCT-08-0854
DOI10.1158/1535-7163.MCT-08-0854
PubMed id19174557
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