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

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), 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 pi (GSTP1), O(6)-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.

• Authors: John P Fruehauf, Henry Brem, Steven Brem, Andrew Sloan, Geoffrey Barger, Weidong Huang, Ricardo Parker
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 15 Pg. 4523-32 (Aug 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16899598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Biomarkers, Tumor
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• Vincristine
• Irinotecan
• Dacarbazine
• DNA Modification Methylases
• MGMT protein, human
• GSTP1 protein, human
• Glutathione S-Transferase pi
• DNA Repair Enzymes
• Paclitaxel
• Cisplatin
• Carmustine
• Camptothecin

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (drug effects, genetics)
• Biomarkers, Tumor (genetics, metabolism)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Camptothecin (analogs & derivatives, pharmacology)
• Carmustine (pharmacology)
• Cisplatin (pharmacology)
• DNA Modification Methylases (drug effects, genetics)
• DNA Repair Enzymes (drug effects, genetics)
• Dacarbazine (pharmacology)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Glioma (drug therapy, metabolism, pathology)
• Glutathione S-Transferase pi (drug effects, genetics)
• Humans
• Immunohistochemistry
• Irinotecan
• Paclitaxel (pharmacology)
• Structure-Activity Relationship
• Tumor Suppressor Protein p53 (drug effects, genetics)
• Tumor Suppressor Proteins (drug effects, genetics)
• Vincristine (pharmacology)