MDR reversal

The multidrug resistance (mdr) reversing effect of the new phenothiazine complexes were tested on mouse T cell lymphoma cell lines. Trifluoperazine (TFP) was much more effective at the same concentration than verapamil. The efficacy of some metal coordination complexes [TFP-Cu(ll) and TFP-V(IV)] exceeded the action of TFP alone. Chlorpromazine (CPZ) or CPZ-Pt(ll) complex had the same or less effect than verapamil or promethazine (Pz) used as a control. 

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... 

Apart from direct interaction of modulators with P-gp their influence on phospholipid bilayer properties was also suggested as an important molecular mechanism responsible for MDR reversal. The vacuum cleaner hypothesis assumes that P-gp substrates are recognized within the lipid phase during their diffusion across the cell membrane. An alteration of lipid phase prop-... 

Unlike the results obtained by Ford and coworkers [188], Molnar et al. [ 192] did not observe the effect of the length of side chain on MDR reversal for other phenothiazine derivatives, i.e., phthalimidophenothiazines. Derivatives with butyl or propyl chains revealed a similar ability to reduce MDR in mouse T lymphoma cells. 

Tsakovska [194] used methods of molecular modeling to investigate a group of 25 phenothiazines and structurally related compounds. The role of hydrophobicity of modulators and hydrogen-bond acceptor interactions in MDR reversal were revealed. The piperazine moiety with a tertiary nitrogen was identified as the most favorable type of side chain for effective MDR modulators. 

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. 

Fig. 3.38 Relation between MDR-reversing activity (ratio, reversal of resistance against doxorubicin) of cis- and trans-flupentixol and their degree of interaction with phospholipid...

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.)...

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. 

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... 

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. 

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