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Drug-resistance gene expression and progression of astrocytic tumors
1Department of Neurosurgery, Kitasato Institute Medical Center Hospital, Kitamoto, Saitama, Japan. tanaka-s@kitasato.or.jp
Abstract:
To clarify the influence of biochemotherapy on the progression of astrocytic tumors, the expression of O6-methylguanine DNA-methyltransferase (MGMT) mRNA, as well as of other drug-resistance- and drug-sensitivity-related genes such as multidrug resistance gene 1, multidrug resistance-associated protein, glutathione S-transferase-pi, DNA topoisomerase II, and interferon receptor mRNA, and the interferon regulatory factor (IRF)-1 and -2 ratios in gliomas were investigated by quantitative reverse transcription-polymerase chain reaction (RT-PCR). The mean MGMT/beta2-microglobulin (beta2-MG) ratio for 130 neuroepithelial tumors was 8.2 +/- 17.8. The mean ratio of 45 glioblastomas was significantly higher than that for the other 85 tumors. In contrast, the mean of 26 low-grade gliomas was significantly lower than that of other tumors. The mean IRF-1/IRF-2 ratio of 16 other brain tumors that mainly consisted of medulloblastomas was significantly greater than that of the other 114 tumors. Almost no significant differences were observed between primary and recurrent tumors in the expression of any gene, and before and after therapy with corresponding drugs. The mean MGMT/beta2-MG ratio in primary glioblastomas was significantly higher than that in secondary tumors. These findings suggest that native drug resistance is more important than acquired resistance when glioma therapy is considered.
Insights
Native drug resistance, indicated by O6-methylguanine DNA-methyltransferase (MGMT) mRNA levels, is more crucial than acquired resistance in glioma therapy. Gene expression analysis in astrocytic tumors revealed significant differences based on tumor grade.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Astrocytic tumors, including glioblastomas and low-grade gliomas, exhibit varying responses to biochemotherapy.
- Drug resistance mechanisms play a critical role in treatment efficacy and tumor progression.
- Understanding gene expression profiles related to drug resistance is essential for optimizing glioma treatment strategies.
Purpose of the Study:
- To investigate the influence of biochemotherapy on astrocytic tumor progression.
- To analyze the expression of drug resistance and sensitivity-related genes, including O6-methylguanine DNA-methyltransferase (MGMT) mRNA, in gliomas.
- To evaluate the ratios of interferon regulatory factor (IRF)-1 and -2 in relation to tumor characteristics and treatment response.
Main Methods:
- Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was employed to measure mRNA expression levels.
- Expression of MGMT, multidrug resistance gene 1, multidrug resistance-associated protein, glutathione S-transferase-pi, DNA topoisomerase II, and interferon receptor mRNA was assessed.
- IRF-1 and IRF-2 ratios were determined and correlated with tumor type, grade, and treatment status.
Main Results:
- The mean MGMT/beta2-microglobulin (beta2-MG) ratio was significantly higher in glioblastomas compared to other neuroepithelial tumors.
- Low-grade gliomas showed a significantly lower mean MGMT/beta2-MG ratio.
- No significant differences in gene expression were observed between primary and recurrent tumors or before and after therapy, suggesting native drug resistance is key.
- Primary glioblastomas had a higher mean MGMT/beta2-MG ratio than secondary glioblastomas.
Conclusions:
- Native drug resistance, particularly related to MGMT expression, is a more significant factor than acquired resistance in the context of glioma therapy.
- Tumor grade strongly correlates with MGMT expression levels, influencing inherent drug resistance.
- Further research into native resistance mechanisms could lead to more effective therapeutic strategies for astrocytic tumors.