In vitro drug response and molecular markers associated with drug resistance in malignant gliomas

John P. Fruehauf, Henry Brem, Steven Brem, Andrew Sloan, Geoffrey Barger, Weidong Huang, Ricardo Parker

Research output: Contribution to journalArticle

Abstract

Purpose: Drug resistance in malignant gliomas contributes to poor clinical outcomes. We determined the in vitro drug response profiles for 478 biopsy specimens from patients with the following malignant glial histologies: astrocytoma (n = 71), anaplastic astrocytoma (n = 39), glioblastoma multiforme (n = 259), oligodendrogtioma (n = 40), and glioma (n = 69). Experimental Design: Samples were tested for drug resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, dacarbazine, paclitaxel, vincristine, and irinotecan. Biomarkers associated with drug resistance were detected by immunohistochemistry, including multidrug resistance gene-1, glutathione S-transferase π (GSTPI), O6-methylguanine-DNA methyltransferase (MGMT), and mutant p53. Results: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMTand GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance. Conclusions: Assessment of in vitro drug response and profiles of relevant tumor-associated biomarkers may assist the clinician in stratifying patient treatment regimens.

Original languageEnglish (US)
Pages (from-to)4523-4532
Number of pages10
JournalClinical Cancer Research
Volume12
Issue number15
DOIs
StatePublished - Aug 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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