DNA topoisomerases, nuclear
enzymes that regulate
DNA topology, are recognized as the primary targets of effective anti-
tumor drugs. These
enzymes may also have a role in the repair of DNA damage induced by
alkylating agents and
platinum compounds; therefore, their expression may be a determinant of
tumor response to
chemotherapy. Our study was undertaken in an attempt to establish a correlation between the
enzyme expression and response of
ovarian cancer to
cisplatin-based
chemotherapy. The expression of
topoisomerase I, II alpha and II beta genes was assessed by
RNase protection assay in
tumor specimens obtained from 37 untreated patients with advanced
epithelial ovarian cancer at initial surgery and from 13 pre-treated patients at subsequent
laparotomy. The expression levels were compared with those found in 5 specimens from benign ovarian tissue and 5 specimens from normal ovarian tissue. The expression levels in untreated patients were used to establish a correlation with response to high-dose
cisplatin therapy. A significant intertumor variability of
mRNA expression was noted for all the genes examined. However, a comparison of median values indicated a remarkable increase of expression in malignant
tumors over benign or normal tissues only for
topoisomerase II alpha. This change is not related to alterations or amplification of
topoisomerase II alpha gene. Interestingly, a correlation was found between
tumor response to
chemotherapy and the expression level of the
isoform alpha (but not of
topoisomerase II beta and
topoisomerase I). The observed correlation suggests a contribution of the
enzyme in determining
tumor sensitivity. Alternatively, increased expression levels of the alpha
isoenzyme gene in responsive
tumors might reflect higher fractions of proliferating
tumor cells that may be more
drug-sensitive than resting cells.