Expression pattern of chemoresistance-related genes in human malignant brain tumors: a working knowledge for proper selection of anticancer drugs.
BACKGROUND
In addition to traditional modalities such as surgical intervention and radiotherapy, chemotherapy is a common therapeutic method for human malignant brain tumors. However, the effectiveness of chemotherapy is frequently hampered by cancer cell chemoresistance, resulting in an unsatisfactory outcome. To overcome this disadvantage, the proper selection of efficacious anticancer agents is required.


METHODS
The expression levels of chemoresistance-related genes, MGMT, mdr1, MRP, MTIIA and GST-pi, in 28 surgical specimens of human brain tumors and in 10 human glioma cell lines were examined by Northern blot analysis. In addition, the SD10 values of human glioma cell lines against ACNU, CDDP, ADM and VP16 were estimated by a cell survival assay.


RESULTS
The expression levels of each of the chemoresistance-related genes, except MRP, were generally higher in brain tumors than those in non-neoplastic brain tissues. MGMT expression correlated exclusively with ACNU resistance in all glioma cell lines examined (p = 0.0002). The transcriptional level of mdr1 in the tumor cells correlated with the SD10 values of VCR (p = 0.04) and ADM (p = 0.034). In contrast, the expression levels of MTIIA and GST-pi did not correlate with resistance to any of the drugs tested. A correlation of MRP mRNA expression with multidrug resistance was not apparent in the 10 cell lines tested.


CONCLUSIONS
The data indicate that knowledge of the expression levels of MGMT and mdr1 may be particularly useful for a more rational selection of drugs which are not influenced by these resistance genes and which have improved efficacy against human brain tumors.
Nagane
M
M
Department of Neurosurgery, National Cancer Center Hospital, Tokyo, Japan.
Asai
A
A
Shibui
S
S
Oyama
H
H
Nomura
K
K
Kuchino
Y
Y
D015703:Antigens, CD / Q000032:analysis / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D019450:Genes, MDR; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008562:Membrane Glycoproteins; D015376:Nimustine / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D060245:Tetraspanin 29; D014407:Tumor Cells, Cultured / Q000187:drug effects
D015703:Antigens, CD; D000970:Antineoplastic Agents; C554869:CD9 protein, human; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D060245:Tetraspanin 29; D015376:Nimustine; D005047:Etoposide; D004317:Doxorubicin; D002945:Cisplatin