Effects of MDR reversing agent combinations on the 3H-daunomycin accumulation in drug-sensitive and drug-resistant human cancer cells.
BACKGROUND
As multidrug resistant (MDR) tumour cells generally exhibit a drug accumulation deficit, the effects of three prototype modulators and their combinations were investigated by studying the modulation of 3H-dounomycin cellular accumulation.


METHODS
Two cell lines derived from a rhino-pharingeal human carcinoma, either sensitive (KB-3-1) or selected as MDR (KB-A1) were used. Verapamil (10mumol.L-1), PSC 833 (lmumol.L-1) and S9788 (5mumol.L-1) were tested alone or in association two by two. The cells were characterized by reverse transcriptase polymerase chain reaction (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 extent. Relative to the KB-3-1, cells, accumulation of 3H-daunomycin was reduced to 31 +/- 5% in the KB-A1 cells. In these KB-A1 cells, the three agents tested significantly increased the 3H-daunomycin intracellular concentration, 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 126 +/- 27%, respectively). On KB-3-1 sensitive cells, S9788 had no effect, while verapamil or PSC 833 moderately increased the 3H-daunomycin accumulation, without additive effect.


CONCLUSIONS
These results show a strong MDR reversing effect of S9788, which appears specific to P-glycoprotein (Pgp) and an additive effect between verapamil and PSC 833, suggesting a better therapeutic efficiency if used in well defined combinations.
Moins
N
N
INSERM U 484, Clermont-Ferrands. moins/***
Cayre
A
A
Chevillard
S
S
Maublant
J
J
Verrelle
P
P
Finat-Duclos
F
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D003524:Cyclosporins / Q000494:pharmacology*; D003630:Daunorubicin / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007624:KB Cells; D010880:Piperidines / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003524:Cyclosporins; D010880:Piperidines; D014227:Triazines; C077022:S 9788; D014700:Verapamil; C070272:valspodar; D003630:Daunorubicin