EFFECTS OF R-ENANTIOMER (GR66234A) AND L-ENANTIOMER (GR66235A) OF TELUPIDINE, A NEW DIHYDROPYRIDINE DERIVATIVE, ON CELL-LINES DISPLAYING THE MULTIDRUG-RESISTANT PHENOTYPE

Background. Many dihydropyridine analogues with calcium channel blocke r activity are able to reverse multidrug resistance (MDR). We studied the daunorubicin resistance reversing activity of the R enantiomer (GR 66234A) and the L-enantiomer (GR66235 A) of teludipine, a new lipophil ic calcium channel blocker synthesized by Glare. Methods. The daunorub icin resistance reversing activity of the enantiomers of teludipine wa s evaluated in two MDR cell lines: ARNII, an erythroleukemia cell line which expresses p-glycoprotein, and MCF 7/R, a breast cancer cell lin e with p-glycoprotein and high levels of glutathione S transferase (GS T) and glutathione peroxidase (GSH Pr). Results. GR66234A and GR66235A show the same activity in reversing daunorubicin resistance and are m ore effective than verapamil. The difference in activity between verap amil and the enantiomers of teludipine is greater in ARNII cells than in MCF 7/R cells. Nevertheless, there are no significative differences in cellular daunorubicin accumulation between ARNII and MCF 7/R follo wing exposure to teludipine, nor are there differences in intracellula r daunorubicin distribution in the presence of either MDR reversing ag ent. Conclusions. The low calcium channel antagonistic activity of GR6 6234A suggests that this compound may be useful in combination with ch emotherapy in MDR malignancies.