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


METHODS
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.
Fruehauf
John P
JP
University of California-Irvine Chao Family Clinical Cancer Research Center, Orange, 92868, USA. jfruehau@uci.edu
Brem
Henry
H
Brem
Steven
S
Sloan
Andrew
A
Barger
Geoffrey
G
Huang
Weidong
W
Parker
Ricardo
R
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D015254:DNA Modification Methylases / Q000187:drug effects / Q000235:genetics; D045643:DNA Repair Enzymes / Q000187:drug effects / Q000235:genetics; D003606:Dacarbazine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051549:Glutathione S-Transferase pi / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D017239:Paclitaxel / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000235:genetics; D014750:Vincristine / Q000494:pharmacology
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014750:Vincristine; D000077146:Irinotecan; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D045643:DNA Repair Enzymes; D017239:Paclitaxel; D002945:Cisplatin; D002330:Carmustine; D002166:Camptothecin