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In vitro Drug Response and Molecular Markers Associated with Drug Resistance in Malignant Gliomas

Authors' Affiliations: ¹ University of California-Irvine Chao Family Clinical Cancer Research Center, Orange, California; ² Johns Hopkins Hospital, Baltimore, Maryland; ³ H. Lee Moffitt Cancer Center, Tampa, Florida; ⁴ Karmanos Cancer Institute and Wayne State University, Detroit, Michigan; and ⁵ Oncotech, Inc., Irvine, California

Requests for reprints: John P. Fruehauf, University of California-Irvine Comprehensive Cancer Center, 101 The City Drive South, Building 23, Orange, CA 92868. Phone: 714-456-7669; Fax: 714-456-7668; E-mail: jfruehau{at}uci.edu.

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), oligodendroglioma (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 (GSTP1), 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%). MGMT and 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.

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