MDR-reversing drugs

Fig. 5.12 Tetracycline resistance-reversing activity of MDR-reversing drugs against coli. +, Control O, tetracycline V, verapamil A, quinacrine , chlorpro-mazine O, trifluoperazine , tetracycline + verapamil , tetracycline + quinacrine , tetracycline + chlorpro-mazine I, tetracycline + trifluoperazine. (Reprinted from Fig. 1 of ref. 64.)...

Change in Composition of Membranes and Influence on P-gp, Cytotoxic Agents, and MDR-Reversing Drugs... 

This argument is further supported by results of a study showing that the potentiation of anticancer drag cytotoxicity by MDR-reversing drugs involves alterations in membrane fluidity, which in turn lead to increases in permeability [109]. The authors could show that the investigated chemosensitizers induced alterations in the bulk membrane fluidity in a dose-dependent manner and in a concentration range... 

The mechanism of modulation of P-gp-mediated MDR remains poorly understood. Several mechanisms of MDR reversal were proposed. Modulators may act as substrates for P-gp and inhibit drug transport in a competitive way. They may also interact with the sites of protein molecules other than... 

Contrary to the results of most quantitative structure-activity relationship (QSAR) studies on phenothiazine type modulators, Dearden et al. [195] found that molecular size, polarity, or polarizability better than other structural features of the compounds correlated with MDR reversing ability, P-gp associated ATPase activity, and inhibition of drug efflux from the blood-brain barrier. They did not find evidence that hydrogen bonding or hydrophobicity played a role in MDR reversal. 

Welwistatin also inhibits cell proliferation with reversible depletion of cellular microtubules in ovarian carcinoma cells and A-10 vascular smooth muscle cells by inhibiting the polymerization of tubulin, but it does not alter the ability of tubulin to bind [3H]colchicine or to hydrolyze GTP [8]. Due to the cytotoxicity associated with the inhibition of tubulin polymerization, which is the main mechanism of action of antitumor drugs such as vincristine and vinblastine, and because P-gp-overexpressing cells show virtually no resistance to welwistatin due to its MDR reversal properties, this natural product could be a good candidate in the chemotherapy of drug-resistant tumors. 

The required structural specificity for the reversing drug is not very high, because drugs with a very different structure and conformation can reverse MDR. 

Currently, several mechanisms of action of M DR-reversing or -modulating drugs are postulated. They are briefly listed and discussed for a better understanding of why drug-membrane interactions as an essential factor in the MDR-reversing process cannot be excluded from the consideration. 

DSC and NMR techniques were used to study the type and degree of interaction between drug and bilayer. The results were compared with those from experiments on the ability of the compounds to reverse MDR in vitro in resistant tumor cell lines. In the DSC experiments, the change in phase transition, Tt and enthalpy, AH, was recorded. Some of the results are summarized in Table 5.15, together with the MDR-reversing activities and PKC inhibitory activity. 

Tab. 5.26 MDR-reversing activity and indicator variables of phenothiazines and related drugs. (Reprinted from Tab. 2 of ref. 152 with permission from Wiley-VCH)...

Many fractions of red and green paprika extracts had reversed the MDR of cancer cells [13,16] in our previous experiments. The effectiveness of hexane and acetone fractions of paprika on the ABC transporter responsible for MDR reversal, made it worth studying the effects of carotenoids and flavonoids on the drug accumulation of cancer cells. 

By comparing the drug uptake by the MDR gene-transfected mouse lymphoma cells in the presence of some selected carotenoids, the carotenoids were classified into three different groups based on MDR reversal activity inactive, moderately active and very active. As shown in Table 1, the... 

Besides the mouse lymphoma cells, the R123 accumulation was also studied in the human breast cancer HTB-26 cells in the presence of carotenoids. The R123 accumulation could not be modified in these cells after carotenoid treatment (Table 2). Because these cancer cells do not contain a MDR efflux pump because the cells have only MDR-related protein (MRP). It is concluded that some carotenoids exert their MDR reversing effect in the human MDR-1 gene-transfected mouse lymphoma cells. However, the same carotenoids did not modify the drug accumulation in the drug-sensitive human breast carcinoma cells (data not shown). It is interesting... 

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

---