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Human multi‐drug‐resistant cancer cells exhibit a high degree of selectivity for stereoisomers of verapamil and quinidine
Author(s) -
Eliason James F.,
Ramuz Henri,
Kaufmann Franz
Publication year - 1990
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910460121
Subject(s) - quinidine , verapamil , vincristine , multiple drug resistance , chemistry , pharmacology , quinine , toxicity , diastereomer , cell culture , in vitro , stereochemistry , medicine , biology , chemotherapy , biochemistry , immunology , organic chemistry , antibiotics , malaria , calcium , cyclophosphamide , genetics
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.