CYTOTOXIC EFFECTS OF A DOXORUBICIN-TRANSFERRIN CONJUGATE IN MULTIDRUG-RESISTANT KB CELLS

Cancer chemotherapy is often limited by the emergence of multidrug-res istant tumor cells. Multidrug resistance (MDR) can be caused by amplif ication of the MDR genes and overexpression of the P-glycoprotein, whi ch is capable of lowering intracellular drug concentrations. A doxorub icin-transferrin conjugate has been synthesized and exerts its cytotox ic effects through a transmembrane mechanism. We have examined the cyt otoxicity of this conjugate and compared it with doxorubicin in sensit ive (KB-3-1) and in multidrug-resistant KB cell lines (KB-8-5, KB-C1, and KB-V1). In the clonogenic assay, doxorubicin exhibited IC50 concen trations of 0.03 and 0.12 mu M in the sensitive (KB-3-1) and resistant (KB-8-5) cell lines, respectively, whereas, doxorubicin-transferrin c onjugate was more effective with IC50 concentrations of 0.006 and 0.02 8 mu M, respectively. In highly multidrug resistant KB-C1 and KB-V1 ce lls, doxorubicin up to 1 mu M did not cause any cytotoxic effects, whi le the doxorubicin-transferrin conjugate inhibited colony formation of these cells with IC50 levels of 0.2 and 0.025 mu M, respectively. The se results demonstrate that doxorubicin-transferrin is effective again st multidrug-resistant tumor cells.