HUMAN HEPATOMA-CELLS RICH IN P-GLYCOPROTEIN ARE SENSITIVE TO ACLARUBICIN AND RESISTANT TO 3 OTHER ANTHRACYCLINES

Drug resistance is a major obstacle to successful chemotherapy of prim ary liver cancer, which is associated with high expression of the mult idrug resistance (MDR) gene product P-glycoprotein (Pgp), a multidrug efflux transporter. The most effective single agents in treatment of p rimary liver carcinoma belong to the anthracycline family, yet several anthracyclines are known to be substrates for Pgp. In the present stu dy, we compared four anthracyclines with respect to cell growth inhibi tion, intracellular accumulation and cellular efflux using the HB8065/ R human hepatoma cell line which is rich in Pgp, and the Pgp-poor pare ntal line HB8065/S. The anthracyclines were also administered in conju nction with the Pgp-modifying agents verapamil and SDZ PSC 833 to asse ss modulation of resistance. The HB8065/R cells were sensitive to acla rubicin (ACL) and highly resistant to epirubicin (EPI), doxorubicin (D OX) and daunorubicin (DNR). SDZ PSC 833 enhanced accumulation, decreas ed efflux and increased cytotoxicity of EPI, DOX and DNR in the HB8065 /R cells, but none of these effects was seen with ACL. In conclusion, ACL is apparently not transported by Pgp and retains its activity in a multidrug-resistant human hepatoma cell line; such properties can be exploited for clinical purposes.