DX-8951f, a water-soluble camptothecin analog, exhibits potent antitumor activity against a human lung cancer cell line and its SN-38-resistant variant

Int J Cancer. 1997 Aug 7;72(4):680-6. doi: 10.1002/(sici)1097-0215(19970807)72:4<680::aid-ijc21>3.0.co;2-e.


We previously reported that DX-8951f, a novel water-soluble camptothecin analog, significantly inhibits the growth of various human and murine tumors in vitro and in vivo. The antitumor effects and topoisomerase I inhibitory activity of DX-8951f are stronger than those of other current camptothecin analogs. In this study, we established an SN-38-resistant cell line, PC-6/SN2-5, from the human oat cell carcinoma PC-6 cell line by a stepwise selection system, investigated the mechanism of resistance of this cell line and then compared the antitumor activity of camptothecin analogs against the cell line. PC-6/SN2-5 cells were resistant to SN-38 (32-fold) and SK&F 104864 (topotecan; 14-fold), but barely resistant to CPT-11 (3-fold) and DX-8951f (2-fold). Topoisomerase I protein levels and topoisomerase I activities of parental cells were similar to those of resistant cells. Determination of the cellular drug concentration by either flow cytometric analysis or the high-performance liquid chromatography method confirmed that the cellular accumulation of SN-38 and topotecan was significantly reduced in PC-6/SN2-5 cells, whereas that of DX-8951f was only slightly reduced. Furthermore, DX-8951f stabilized the cleavable complex formations in intact PC-6/SN2-5 cells as well as in parental cells, but SN-38 and topotecan did not in the resistant cells. Our data suggest that PC-6/SN2-5 cells may have acquired resistance to camptothecin analogs by a decrease in intracellular drug accumulation and that DX-8951f may have the potency to overcome such a type of resistance mechanism induced by camptothecin compounds.

MeSH terms

  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology
  • Carcinoma, Small Cell / drug therapy*
  • Carcinoma, Small Cell / metabolism
  • DNA Topoisomerases, Type I / metabolism
  • DNA, Neoplasm / metabolism
  • Drug Resistance, Neoplasm
  • Drug Stability
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Humans
  • Irinotecan
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Solubility
  • Topoisomerase I Inhibitors
  • Topotecan
  • Tumor Cells, Cultured
  • Water


  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • DNA, Neoplasm
  • Enzyme Inhibitors
  • Topoisomerase I Inhibitors
  • Water
  • Irinotecan
  • Topotecan
  • DNA Topoisomerases, Type I
  • exatecan
  • Camptothecin