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

Abstract

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) alpha and beta mRNA in MBs. In addition, the levels of Topo IIalpha and beta mRNA in these tumors correlated with etoposide sensitivity. Immunohistochemical studies using surgical samples of these tumors demonstrated that the percentages of Topo IIalpha immunopositive cells (Topo IIalpha labeling index) correlated with those of Ki-67 immunopositive cells (MIB-1 labeling index); however, neither the Topo IIalpha nor the MIB-1 labeling index correlated with the levels of Topo IIalpha mRNA or etoposide sensitivity. Based on these observations, Topo IIalpha and beta mRNA expression, but not the Topo IIalpha labeling index, might be a useful marker for sensitivity to etoposide in human malignant neuroepithelial tumors.