TY - JOUR
T1 - In vitro drug response and molecular markers associated with drug resistance in malignant gliomas
AU - Fruehauf, John P.
AU - Brem, Henry
AU - Brem, Steven
AU - Sloan, Andrew
AU - Barger, Geoffrey
AU - Huang, Weidong
AU - Parker, Ricardo
PY - 2006/8/1
Y1 - 2006/8/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-05-1830
DO - 10.1158/1078-0432.CCR-05-1830
M3 - Article
C2 - 16899598
AN - SCOPUS:33748056466
SN - 1078-0432
VL - 12
SP - 4523
EP - 4532
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -