EVALUATION OF TOPOISOMERASE-I CATALYTIC ACTIVITY AS DETERMINANT OF DRUG RESPONSE IN HUMAN CANCER CELL-LINES

The prognostic value of topoisomerase I (Topo I) catalytic activity an d expression of the multidrug resistance (MDR) marker P-glycoprotein ( Pgp) and multidrug resistance protein (MRP) for in vitro, sensitivity to Topo I interactive agents were evaluated. The efficacy of short ter m (2 h) and long term (24 h) exposures of camptothecin (CPT), two CPT derivatives (SN-22, SN-38) and the indolocarbazole compound NB-506, wa s deter-mined against human ovarian carcinoma (A2780 and A2780 DX5), h uman fibrosarcoma (HT1080 and IIT2080/DR4) and human ileocecal carcino ma (HCT-8). For each cell line the Topo I protein levels and catalytic activity were determined and correlated with drug-induced cytotoxicit y. In general the Topo I protein levels correlated with Topo I catalyt ic activity. Drug-induced cytotoxicity increased significantly with pr olongation of the exposure time. With the 2 h exposure, the multidrug resistant A2780 DX5 cell line (Pgp+, MRP-) was moderately resistant to all four drugs compared to its parental cell line. in case of CPT and SN-22 but not for SN-38 and NB-506, this resistance was no longer det ectable following 24 h drug exposure. No resistance was detectable for the multidrug resistant HT1080/DR4 (Pgp-, MRP+) cell line when compar ed to its parental cell line. With short term exposures a strong trend was observed toward increased cytotoxicity with increased Topo I cata lytic activity.