Enhanced expression of DNA topoisomerase II genes in human medulloblastoma and its possible association with etoposide sensitivity

Medulloblastoma (MB) is the most common malignant neuroepithelial tumor of childhood. The DNA topoisomerase II (Topo II) inhibitor etoposide has been widely used for the treatment of MBs; however, it remains unknown whether MB cells are more sensitive to etoposide than other malignant neuroepithelial tumor cells. In this study, we tested the chemosensitivities of malignant neuroepithelial tumors (26 glioblastomas, 9 anaplastic astrocytomas, and 5 MBs) to etoposide and vincristine using the succinate dehydrogenase inhibition test and found that MB cells are more sensitive to etoposide and more resistant to vincristine than other tumor cells. We performed quantitative reverse-transcription polymerase chain reaction to evaluate the expression of genes related to etoposide sensitivity, and found co-overexpression of DNA topoisomerase II (Topo II) α and β mRNA in MBs. In addition, the levels of Topo IIα and β mRNA in these tumors correlated with etoposide sensitivity. Immunohistochemical studies using surgical samples of these tumors demonstrated that the percentages of Topo IIα immunopositive cells (Topo IIα labeling index) correlated with those of Ki-67 immunopositive cells (MIB-1 labeling index); however, neither the Topo IIα nor the MIB-1 labeling index correlated with the levels of Topo IIα mRNA or etoposide sensitivity. Based on these observations, Topo IIα and β mRNA expression, but not the Topo IIα labeling index, might be a useful marker for sensitivity to etoposide in human malignant neuroepithelial tumors.