REVERSAL OF MULTIDRUG-RESISTANCE BY VERAPAMIL ANALOGS

The basic distinguishing feature of multidrug resistant (MDR) cells is a decrease in steady-state drug levels as compared to drug-sensitive controls. It is well-known that verapamil increases the sensitivity of MDR cells to drugs, thus reverting drug resistance. A limiting factor for its clinical use is the pronounced cardiovascular effects of the calcium channel antagonist which occur at the high plasma concentratio ns required to block P-glycoprotein transport efficiently. From a clin ical point of view, it is important to find verapamil derivatives with low calcium channel blocking activity and high reverting activity. Th is was the aim of the present study. In this context we have investiga ted the ability of 20 verapamil analogues with restricted molecular fl exibility to increase cellular accumulation of anticancer drugs and ov ercome resistance, and their inotropic, chronotropic, and slow calcium channel antagonistic activity. In this study an anthracycline derivat ive 4'-O-tetrahydropyranyl adriamycin, and an erythroleukaemia K562 ce ll line were used. Three of the 20 derivatives checked were completely devoid of calcium channel blocking activity while exhibiting MDR reve rting ability comparable to that of verapamil. These derivatives could be useful for the treatment of MDR in cancer patients and for the des ign and development of other verapamil derivatives.