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The relationship between DNA topoisomerase II (Topo II) expression and human ovarian cancer has been evaluated by analyzing the enzyme activity, enzyme levels, and expression of mRNA of DNA Topo II isozymes, α and β, in normal (n = 4), benign (5 serous cystadenomas), and malignant (29 serous adenocarcinomas, stages I-III) human ovarian cells, selected from G2M-S phase fractions of similar numbers of cells in the corresponding tissues. By the P4 DNA-unknotting assay, the elevation of DNA Topo II α activity in 29 cases was found to be 2 to 3 times greater than that of normal ovarian tissues. An average 2- to 4-fold increase in the expression of the immunoreactive DNA Topo II α was also revealed by immunoblot analysis in G2M-S phase fractions of cells in the 29 cases of ovarian cancer. A good correlation between catalytic activity of the enzyme and its level in the corresponding tumor tissue was also found. Topo II mRNA levels were found by northern blot coupled with RT-PCR analysis to be increased significantly. An average 5.2-7.2 fold increase of DNA Topo II α mRNA was found in the corresponding cases of stage I-III G2M-S phase fractions of ovarian adenocarcinomas, compared to normal matched ovarian tissue. Eight of 29 malignant ovarian cancer tissues did not show significantly elevated expression of α isoform. No significant changes were found in the activity and expression of β isozyme in various stages of ovarian cancer. The results suggest that the increase in enzyme levels in some advanced ovarian cancer may result from either increased transcription of Topo II α gene or increased mRNA stability. It also suggests the potential usefulness of chemotherapeutic agents targeting DNA Topo II α expressed in some ovarian cancers.