REVERSAL EFFECTS OF SEVERAL CA2-ENTRY BLOCKERS, NEUROLEPTICS AND LOCAL-ANESTHETICS ON P-GLYCOPROTEIN-MEDIATED VINCRISTINE RESISTANCE OF L1210()VCR MOUSE LEUKEMIC-CELL LINE/

The ability of several Ca2+-entry blockers, neuroleptics and local ana esthetics to depress the P-glycoprotein-mediated resistance to vincris tine was studied in vitro using the L1210/VCR cell line. This cell lin e was obtained by long-term adaptation of the L1210 moose leukaemic ce ll line on vincristine and showed an overexpression of P-glycoprotein and accompanying multidrug resistance (MDR) which was defined as a cel l resistance to several cytostatics such as vincristine, vinblastine a nd actinomycin D. Efficiency of the drugs applied to reverse this resi stance was as follows: for Ca2+-entry blockers: verapamil (VER) greate r than or equal to galopamil (GAL) > flunarizine (FLU) >> diltiazem (D IL) > nimodipine (NIM) greater than or equal to nifedipine (NIM); for neuroleptics: trifluoperazine (TFP) > chlorpromazine (CHP) > thioridaz ine (TRD) > perphenazine (PER); for local anaesthetics: carbanilate-Ca 7 > cinchocaine (CIN) >> carbanilate-Ca3 > articaine (ART) > carbanila te CAO > lidocaine (LID). Quaternary cabanilate derivatives (Ca7Q and Ca3Q) with permanent positive charge were found to be unable to revers e the vincristine resistance of L1210/VCR cells. No reasonable correla tion between the ability of calcium-entry blockers (DIL, VER, GAL, NIF , NIM and FLU) to reduce the viability of L1210/VCR cells growing in t he medium supplemented with vincristine and their reported affinity to the L-type of calcium channel was observed. On the other hand, signif icant positive correlations were observed between both the inhibitory action of local anaesthetics on propagation of action potential in rat sciatic nerve and the ability of drugs to interact with calmodulin an d the ability of the respective drug to reverse the resistance of L121 0 cells to vincristine.