Elevated topoisomerase I activity in cervical cancer as a target for chemoradiation therapy.

OBJECTIVE The aim of this study was to determine whether the activity of topoisomerase I (topo I), the target of the anti-neoplastic drug camptothecin (CPT), is elevated in cervical cancer and whether CPT can radiosensitize cervical tumors. METHODS The topo I activity of 11 normal cervix and 30 cervical carcinoma tumors was assayed by measuring the relaxation of supercoiled DNA. Subconfluent or postconfluent CaSki human cervical carcinoma cells were exposed to CPT (1-5000 ng/ml) and immediately X-irradiated (0-800 cGy). Cell survival was determined by clonogenic assay. RESULTS Mean topo I activity in cervical cancer (3.0 +/- 0.06 h(-1)) was significantly greater than in normal cervix tissue (0.29 +/- 0.06 h(-1)). Stage 3 and 4 cervical carcinoma specimens displayed a trend of greater topo I activity (5.88 +/- 3.7 h(-1)) than stage 1 and 2 tumors (2.57 +/- 0.47 h(-1)). No correlation between topo I protein levels and catalytic activity was found. Combined treatment of subconfluent CaSki cells with CPT and ionizing radiation resulted in additive killing of cells. Combined treatment of postconfluent CaSki cells with low doses of radiation (200 and 400 cGy) and 1 or 10 ng/ml CPT for 2 or 48 h produced significant cytotoxicity compared to CPT or radiation alone, which were ineffective at these doses. CONCLUSIONS Topo I activity is elevated in cervical cancer compared to normal cervix. The radiosensitivity of noncycling cells within cervical tumors may be increased by simultaneous treatment with low doses of CPT or other topo I inhibitors.