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 t opoisomerase I (topo I), the target of the anti-neoplastic drug camptotheci n (CPT), is elevated in cervical cancer and whether CPT can radiosensitize cervical tumors. Methods. The topo I activity of 11 normal cenix and 30 cervical carcinoma t umors was assayed by measuring the relaxation of supercoiled DNA, Subconflu ent or postconfluent CaSki human cervical carcinoma cells were exposed to C PT (1-5000 ng/ml) and immediately X-irradiated (0-800 cGy), Cell survival w as determined by clonogenic assay. Results. Mean topo I activity in cervical cancer (3.0 +/- 0.06 h(-1)) was s ignificantly greater than in normal cenix tissue (0.29 +/- 0.06 h(-1)). Sta ge 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 wa s found. Combined treatment of subconfluent CaSki cells with CPT and ionizi ng radiation resulted in additive killing of cells. Combined treatment of p ostconfluent 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 nor mal 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. (C) 2000 Academic Press.