Effects of MDR reversing agent combinations on the H-3-daunomycin accumulation in drug-sensitive and drug-resistant human cancer cells

Background: As multidrug resistant (MDR) tumour cells generally exhibit a d rug accumulation deficit, the effects of three prototype modulators and the ir combinations were investigated by studying the modulation of H-3-daunomy cin cellular accumulation. Materials and Methods: Two cell lines derived fr om a rhino-pharingeal human carcinoma, either sensitive (KB-3-1) or selecte d as MDR (KB-A1) were used. Verapamil (10 mu mol.L-1), PSC 833 (1 mu mol.L- 1) and S9788 (5 mu mol.L-1) were tested alone or in association two by two The cells were characterized by reverse transcriptase polymerase chain reac tion (RT-PCR) in terms of pleiotropic resistance gene expression. Results: A strong mdr1 and a light LRP gene expression were found in KB-A1 resistant cells compared to KB-3-1, whereas MRP expression was found to a similar ex tent. Relative to the KB-3-1 cells, accumulation of H-3-daunomycin was redu ced to 31+/-5 % in the KB-A1 cells. In these KB-A1 cells the three agents t ested significantly increased the H-3-daunomycin intracellular concentratio n, S9788 being the most active (311 +/- 37 %) and inducing a near complete reversion to the basal level of the sensitive cells. Verapamil and PSC 833 demonstrated an additive effect (252 +/- 69% compared to 188 +/- 33% and 12 6 +/- 27%, respectively). On KB-3-1 sensitive cells, S9788 had no effect wh ile verapamil or PSC 833 moderately increased the H-3-daunomycin accumulati on, without additive effect. Conclusion: These results show a strong MDR re versing effect of S9788, which appears specific to P-glycoprotein (Pgp) and an additive effect between verapamil and PSC 833, suggesting a better ther apeutic efficiency if used in well defined combinations.