Dithiane analogues of
tiapamil are highly active as modifiers of
P-glycoprotein mediated multidrug resistance (MDR) in vitro. In an assay using the
P-glycoprotein over-expressing cell line KB-8-5, the most active analogues for decreasing
vincristine resistance were the racemate
Ro 11-5160 and its two enantiomers,
Ro 44-5911 (R) and
Ro 44-5912 (S). In the KB-8-5 assay, the resistance modification index (RMI) of
Ro 11-5160 was approximately 12-fold higher than those of the most active reference compounds tested,
dipyridamole,
cepharanthine,
reserpine and
cyclosporin A, when compared at concentrations equal to one-tenth of the IC50 of each compound (RMI0.1). The enantiomers have similar resistance modifying activities, but the (S) enantiomer
Ro 44-5912 is somewhat more active, fully reverting the
vincristine sensitivity of KB-8-5 cells to the level of the parental KB-3-1 cells at a concentration of 2 microM. The (R) enantiomer attained this level of modification at a concentration of 3.5 microM. These concentrations are both well below their IC50 values for KB-8-5 cells (150 microM). The enantiomers appear to interact with
P-glycoprotein because they inhibited [3H]
azidopine and [3H]-
vinblastine binding to plasma membrane fractions prepared from resistant K562/ADR cells. However, in addition to their resistance modifying activities with KB-8-5 cells, these compounds also decreased the IC50 values of
vincristine and
doxorubicin with KB-3-1 cells that do not express detectable levels of
P-glycoprotein.
Ro 44-5911 overcame
doxorubicin and
vincristine resistance in three
colorectal cancer cell lines (DLD-1, WiDr and COLO 201) that express
P-glycoprotein. No effect was seen with the 3 colorectal cell lines on the IC50 values of three drugs not related to the MDR phenotype,
5-fluorouracil,
5'-deoxy-5-fluorouridine and cis-diaminodichloroplatinum (II). The in vitro vasodilatory activity of these dithianes, measured with strips of rat aorta contracted with KCl, was about 5% of that of
verapamil. These results suggest that diathianes could be useful agents for MDR modification in vivo.