Evaluation of topoisomerase I catalytic activity as determinant of drug response in human cancer cell lines

Anticancer Res. Sep-Oct 1997;17(5A):3707-11.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology*
  • Carbazoles / pharmacology
  • Catalysis
  • DNA Topoisomerases, Type I / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Glucosides / pharmacology
  • Humans
  • Irinotecan
  • Topoisomerase I Inhibitors
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents, Phytogenic
  • Carbazoles
  • Enzyme Inhibitors
  • Glucosides
  • NB 506
  • Topoisomerase I Inhibitors
  • Irinotecan
  • 7-ethylcamptothecin
  • DNA Topoisomerases, Type I
  • Camptothecin