An enhanced active efflux of CPT-11 and SN-38 in cisplatin-resistant human KB carcinoma cells

Cancer Lett. 1999 Apr 26;138(1-2):13-22. doi: 10.1016/s0304-3835(98)00367-x.


Cisplatin-resistant KCP-4 cells were 12.4- and 31.6-fold more resistant to CPT-11 and SN-38 than parental KB-3-1 cells, respectively. We studied the mechanism of cross-resistance to CPT-11 and SN-38. Our previous study showed that multidrug resistance protein (MRP), canalicular multispecific organic anion transporter (cMOAT) and P-glycoprotein (P-gp) were not expressed in KCP-4 cells (Chen, Z.-S. et al., Exp. Cell Res., 240 (1998) 312-320, and Chuman, Y. et al., Biochem. Biophys. Res. Commun., 226 (1996) 158-165). The accumulation of both CPT-11 and SN-38 in KCP-4 cells was lower than that in KB-3-1 cells. The ATP-dependent efflux of CPT-11 and SN-38 from KCP-4 cells was enhanced compared with that from KB-3-1 cells. DNA topoisomerase (topo) I expression, topo I activity, topo I-mediated cleavable complex, and the sensitivity to SN-38 of DNA topo I in KCP-4 were similar to those in KB-3-1 cells. Furthermore, the conversion of CPT-11 to SN-38 in the two cell lines was also similar. The transport of LTC4 in KCP-4 membrane vesicles was competitively inhibited by bis-(glutathionato)-platinum (II) (GS-Pt), CPT-11 and SN-38. These findings suggested that an unknown transporter distinct from P-gp, MRP or cMOAT is expressed in KCP-4 cells and transports CPT-11 and SN-38.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / analysis
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology
  • Cisplatin / pharmacology*
  • DNA / metabolism
  • DNA Topoisomerases, Type I / metabolism
  • Drug Resistance, Neoplasm
  • Humans
  • Irinotecan
  • KB Cells
  • Leukotriene C4 / pharmacokinetics
  • Multidrug Resistance-Associated Proteins


  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Multidrug Resistance-Associated Proteins
  • Leukotriene C4
  • Irinotecan
  • DNA
  • DNA Topoisomerases, Type I
  • Cisplatin
  • Camptothecin