MDR reversal agents

Fig. 9 Structures of various classes of drugs used as MDR reversal agents...

Furthermore, the expression and function of the Pgp can be modulated by indirect mechanisms, such as interactions with membrane lipids [67] or inhibition of protein kinase C. The reversal of MDR is established using tumor cells lines that are made resistant by the exposure to an anticancer agent or by transfection of the mdrl or mrpl genes. The parameter most widely used to show the activity of MDR reversal agents is reversal factor (RF). This type of assay assumes that the reversal agent does not show inherent cytotoxicity at the concentrations tested. 

Some members of calcium channel blockers, such as nicardipine (40) and ni-modipine (41), were identified as potent MDR antagonists. This early work stressed the lack of correlation between the calcium channel blocking and anti-MDR potencies [75]. It has been reported that DHPs bind to a site that is allosterically coupled to the receptor site which binds anticancer agents and other MDR reversal agents [76,77]. DHPs are well recognized as privileged structure for their multi-receptor affinity [78,79]. 

Two isomers of teludipine (54), R-enantiomer (GR66234A) and L-cn-antiomer (GR66235 A) which were originally developed as a new lipophilic calcium channel blocker by Glaxo were evaluated for daunorubicin resistance reversal activity and found to be more effective than verapamil. Additionally, the difference in activity was also found on different cells. Verapamil and the enantiomers of teludipine are more active in ARNII cells than in MCF 7/R cells. There were no apparent differences in cellular daunorubicin accumulation between ARNII and MCF 7/R following exposure to teludipine and no differences in intracellular daunorubicin distribution in the presence of either MDR reversing agent were observed [97]. 

Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T. 1993. P-glycoprotein-mediated transcellular transport of MDR-reversing agents. FEBSLett. 324 99-102... 

It is expected that the introduction of inhibitors of bacterial RND transporters as anti-infective agents might be more expeditious than for MDR-reversing agents for cancer therapy, since no close human homologues exist and therefore no target-based toxicity is expected. 

The clinical efficacy of MDR reversal agents is less proven. A number of clinical trials have led to unsatisfactory outcomes [37] with several eauses of failure identified. Because the first-generation agents often require high doses to... 

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