REVERSAL OF MULTIDRUG-RESISTANCE BY NEW DIHYDROPYRIDINES WITH LOW-CALCIUM ANTAGONIST ACTIVITY

The clinical use of Ca++ antagonist agents as modulators of multidrug resistance is limited by their strong vasodilator activity. This study reports data obtained by testing a series of new 1,4 dihydropyridine derivatives (DHPs) for their in vitro resistance modulating activity a nd their Ca++ antagonist effect. All the tested DHPs are active to inc rease doxorubicin activity with dose modifying factor values ranging b etween 2 and 47 on P388/DX cells and 12 and 36 on LoVo/DX cells. Their resistance modulating action is exerted through an increase of DX int racellular level. The Ca++ antagonist activity of DHPs, evaluated as c apacity to inhibit the KCl-induced contractions in isolated Guinea pig ileum strips, is not related to their resistance modulating activity. This finding makes it possible to select, for further in vivo evaluat ions, compounds IX, X and XI, which have strong ability to overcome mu ltidrug resistance and low Ca++ antagonist effect.