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 m
echanism 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 nor expressed in
KCP-4 cells (Chen, Z.-S. et al., Exp. Cell Res., 240 (1998) 312-320, and Ch
uman, Y. et al., Biochem. Biophys. Res. Commun., 226 (1996) 158-165). The a
ccumulation 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 lin
es was also similar. The transport of LTC4 in KCP-4 membrane vesicles was c
ompetitively inhibited by bis-(glutathionato)platinum (II) (GS-Pt), CPT-11
and SN-38. These findings suggested that an unknown transporter distinct fr
om P-gp, MRP or cMOAT is expressed in KCP-3 cells and transports CPT-11 and
SN-38. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.