Journal article
Evaluation of topoisomerase I catalytic activity as determinant of drug response in human cancer cell lines
Anticancer research, Vol.17(5A), pp.3707-3711
1997
PMID: 9413228
Abstract
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.
Details
- Title: Subtitle
- Evaluation of topoisomerase I catalytic activity as determinant of drug response in human cancer cell lines
- Creators
- W Voigt - Martin-Luther-Universität Halle-Wittenberg, Klinikum Kröllwitz, Department of Hematology/Oncology, Ernst-Grube Str. 40, 06120 Halle/Saale, GermanyU Vanhoefer - West German Cancer Center, University of Essen, Hufelandstrasse, 45122 Essen, GermanyM. B Yin - Roswell Park Cancer InstituteH Minderman - Roswell Park Cancer InstituteH. J Schmoll - Martin-Luther-Universität Halle-Wittenberg, Klinikum Kröllwitz, Department of Hematology/Oncology, Ernst-Grube Str. 40, 06120 Halle/Saale, GermanyY. M Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Anticancer research, Vol.17(5A), pp.3707-3711
- Publisher
- International Institute of Anticancer Research
- PMID
- 9413228
- ISSN
- 0250-7005
- eISSN
- 1791-7530
- Language
- English
- Date published
- 1997
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359903602771
Metrics
5 Record Views