The prognostic value of
topoisomerase I (
Topo I) catalytic activity and 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 term (2 h) and long term (24 h) exposures of
camptothecin (
CPT), two
CPT derivatives (SN-22, SN-38) and the indolocarbazole compound
NB-506, was determined against human ovarian
carcinoma (A2780 and A2780 DX5), human
fibrosarcoma (HT1080 and IIT1080/DR4) and human ileocecal
carcinoma (HCT-8). For each cell line the
Topo I
protein levels and catalytic activity were determined and correlated with
drug-induced cytotoxicity. In general, the
Topo I
protein levels correlated with
Topo I catalytic activity.
Drug-induced cytotoxicity increased significantly with prolongation 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 detectable following 24 h
drug exposure. No resistance was detectable for the multidrug resistant HT1080/DR4 (Pgp-, MRP+) cell line when compared to its parental cell line. With short term exposures a strong trend was observed toward increased cytotoxicity with increased
Topo I catalytic activity, especially if this correlation was studied between derivative cell lines (A2780 vs. A2780 DX5 and HT1080 vs. HT1080/DR4). This correlation weakened when all 5 cell lines and both exposure conditions were considered. Thus, although overall the correlation between
Topo I catalytic activity and sensitivity to
Topo I interactive drugs between different cell lines is weak, this correlation may be stronger when comparing derivative cell lines. For
CPT and
SN-22 but not for
SN-38 and
NB-506, the moderate resistance levels observed in the Pgp-expressing cell line could be negated by prolongation of exposure duration. MRP expression did not effect
drug efficacy. The data demonstrate that the importance of
Topo I catalytic activity as single prognostic factor for
drug response to
Topo I interactive agents is weak and that additional mechanisms affecting
drug response have to be taken into consideration.