GENE-EXPRESSION OF DNA-TOPOISOMERASE- I, DNA-TOPOISOMERASE-II-ALPHA AND DNA-TOPOISOMERASE-II-BETA AND RESPONSE TO CISPLATIN-BASED CHEMOTHERAPY IN ADVANCED OVARIAN-CARCINOMA

DNA topoisomerases, nuclear enzymes that regulate DNA topology, are re cognized as the primary targets of effective anti-tumor drugs. These e nzymes may also have a role in the repair of DNA damage induced by alk ylating agents and platinum compounds; therefore, their expression may be a determinant of tumor response to chemotherapy. Our study was und ertaken in an attempt to establish a correlation between the enzyme ex pression and response of ovarian cancer to cisplatin-based chemotherap y. The expression of topoisomerase I, II alpha and II beta genes was a ssessed 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 corre lation with response to high-dose cisplatin therapy. A significant int ertumor variability of mRNA expression was noted for all the genes exa mined. However, a comparison of median values indicated a remarkable i ncrease of expression in malignant tumors over benign or normal tissue s only for topoisomerase II alpha. This change is not related to alter ations or amplification of topoisomerase II alpha gene. Interestingly, a correlation was found between tumor response to chemotherapy and th e expression level of the isoform alpha (but not of topoisomerase II b eta and topoisomerase I). The observed correlation suggests a contribu tion of the enzyme in determining tumor sensitivity. Alternatively, in creased expression levels of the alpha isoenzyme gene in responsive tu mors might reflect higher fractions of proliferating tumor cells that may be more drug-sensitive than resting cells. (C) 1996 Wiley-Liss, In c.