NOVEL DITHIANE ANALOGS OF TIAPAMIL WITH HIGH-ACTIVITY TO OVERCOME MULTIDRUG-RESISTANCE IN-VITRO

Dithiane analogues of tiapamil are highly active as modifiers of P-gly coprotein mediated multidrug resistance (MDR) in vitro. In an assay us ing the P-glycoprotein over-expressing cell line KB-8-5, the most acti ve analogues for decreasing vincristine resistance were the racemate R o 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 re ference compounds tested, dipyridamole, cepharanthine, reserpine and c yclosporin A, when compared at concentrations equal to one-tenth of th e IC50 Of each compound (RMI(0.1)). The enantiomers have similar resis tance modifying activities, but the (S) enantiomer Ro 44-5912 is somew hat 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 mu M. The (R) enantiomer attained this level of modification at a c oncentration of 3.5 mu M. These concentrations are both well below the ir IC50 values for KB-8-5 cells (150 mu M). The enantiomers appear to interact with P-glycoprotein because they inhibited [H-3]azidopine and [H-3]-vinblastine binding to plasma membrane fractions prepared from resistant K562/ADR cells. However, in addition to their resistance mod ifying activities with KB-8-5 cells, these compounds also decreased th e IC50, values of vincristine and doxorubicin with KB-3-1 cells that d o not express detectable levels of P-glycoprotein. Ro 44-5911 overcame doxorubicin and vincristine resistance in three colorectal cancer cel l lines (DLD-1, WiDr and COLO 201) that express P-glycoprotein. No eff ect was seen with the 3 colorectal cell lines on the IC50 values of th ree drugs not related to the MDR phenotype, 5-fluorouracil, 5'-deoxy-5 -fluorouridine and cis-diaminodichloroplatinum (II). The in vitro vase dilatory activity of these dithianes, measured with strips of rat aor ta contracted with KCl, was about 5% of that of verapamil. These resul ts suggest that dithianes could be useful agents for MDR modification in vivo.