title: Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines.
abstract: 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.
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Clarke
authors.forename: Evan A
authors.initials: EA
authors.lastname: Mulligan
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Grogan
authors.forename: Ann C
authors.initials: AC
authors.lastname: Mladek
authors.forename: Brett L
authors.initials: BL
authors.lastname: Carlson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Schroeder
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
authors.forename: Paul A
authors.initials: PA
authors.lastname: Decker
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.forename: E Ruth
authors.initials: ER
authors.lastname: Plummer
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; C521013:veliparib; D003606:Dacarbazine; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide