Human multi-drug-resistant cancer cells exhibit a high degree of selectivity for stereoisomers of verapamil and quinidine

✍ Scribed by James F. Eliason; Henri Ramuz; Franz Kaufmann

• Publisher: John Wiley and Sons
• Year: 1990
• Tongue: French
• Weight: 511 KB
• Volume: 46
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910460121

✦ Synopsis

Abstract

An in vitro cell proliferation assay was developed to measure the capacity of substances to overcome multi‐drug resistance (MDR). The assay is a modification of the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) method. The inclusion of cell titration curves for each concentration of the resistance modifier (RM) allows the IC~50~ of the RM to be calculated and provides empirical correction of the cell survival curves for the effect of the RM when it is combined with a standard cytotoxic drug, vincristine. The resistance modification index (RMI) is defined as the ratio of the IC~50~ of vincristine obtained in control cultures divided by that measured in the presence of RM and is linearly related to the dose of RM. The RMI~0.1~, the RMI at a one‐tenth the IC~50~ of the RM, provides a relative comparison between the activities of different RMs at non‐toxic doses. The results obtained using the MDR cell line, KB‐8‐5, show that I‐(‐)‐verapamil is approximately 4 times more active than d‐(+)‐verapamil in modifying MDR. The racemic mixture has an intermediate activity. A similar comparison between the epimers quinidine and quinine shows that, at equimolar doses, quinine has a higher RMI but, because it is more toxic, the RMI~0.1~ is about one‐half of that of quinidine. These results demonstrate the importance of comparing the resistance‐modifying activities of different compounds at doses relative to their own toxicity.