Abstract
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. 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. 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. 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.
Highlights
The persistent invasiveness of malignant gliomas into the surrounding normal brain parenchyma including eloquent regions (l) renders surgical intervention and/or radiotherapy insufficient for curative therapy
We have measured the expression levels of five chemoresistance-related genes in human brain tumors and human glioma cell lines and the SDIO values of glioma cell lines treated with chemotherapeutic agents such as ACNU, VCR, ADM, CDDP and VPI6
The ACNU resistance of glioma cells did not correlate with the expression levels of other chemoresistance-related genes such as glutathione S-transferase (GST)-TC (p = 0.555)
Summary
The persistent invasiveness of malignant gliomas into the surrounding normal brain parenchyma including eloquent regions (l) renders surgical intervention and/or radiotherapy insufficient for curative therapy. The ineffectiveness of brain tumor chemotherapy could result in part from the low efficiency of the penetration of a drug through the blood-brain barrier (BBB), resulting in a reduced, non-cytotoxic local drug concentration [3]. Another potential reason for chemotherapeutic ineffectiveness could lie in the tumor cell chemoresistance, either intrinsic or acquired, and further in the Chemoresistance of human brain tumors intertumoral variation of chemosensitivity to anticancer agents. Methods: The expression levels of chemoresistance-related genes, MGMT, mdr, MRP, MTIIA and GST-n, in 28 surgical specimens of human brain tumors and in 10 human glioma cell lines were examined by Northern blot analysis.
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