MDR phenotype

Acquired resistance has been observed by constitutive upregulation of mdr efflux pump expression due to a mutation inactivating a respective repressor or inducibly, caused by molecules transiently inactivating repressor molecules upon binding. Depending upon the substrate spectra of the respective subset of efflux pumps upregulated, a multiple drug resistance (mdr) phenotype is expressed, which in combination with a specific resistance mechanism can contribute to a clinically relevant level of resistance. 

The vinca alkaloids vinblastine and vincristine are capable of producing the MDR phenotype in a wide variety of cell types. Furthermore, cells that are made resistant to antitumor drugs such as doxorubicin, actinomy-cin D, or the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26) are often resistant to the effects of the bisindole alkaloids. The structural and mechanistic diversity of these compounds is even more striking against the backdrop of collateral resistance. 

It is worthy of note that the activity against MCF7-R expressing MDR phenotype is very sensitive to the structure of the C-10 modifier, while this structural variation generally has little effect on the activity against the normal cancer cell lines. The fact clearly indicates that there is no apparent correlation between the activities of the taxoids against the normal cancer cell lines and the drug-resistant cell line. 

P-gp was initially discovered by Juliano and Ling as a TM protein, which was overexpressed in CHO cells that had acquired resistance to the effects of cytotoxic dmgs (1,2). In several cancerous tissues, overexpression of P-gp often is associated with conferring the MDR phenotype that involves cellular insensitivity to a variety... 

Although a precise understanding of the implications of P-gp interactions is yet to be realized, some insight into how coadministration of substrates and inhibitors interact can be gained from clinical findings. The first area involves attempts to reverse the MDR phenotype via P-gp inhibition. The second area involves reports of DDIs potentially mediated by P-gp. A summary of the findings in each area and conclusions around P-gp interactions that they provide is given below. 

Resistance to paclitaxel has been described in cultured cells, and it appears in several forms. In one, resistance is associated with altered expression or mutation in a- and (3-tubulins [148,149], whereas in another, paclitaxel resistance is associated with overexpression of Pgp and the MDR phenotype [150]. 

Resistance to vinca alkaloids can be mediated by glycoprotein B, a transmembrane pump that is part of the multidrug resistance (MDR) phenotype (5). 

McLeod, H. L. (1994) Clinical reversal of the MDR phenotype true tumour modulation or pharmacokinetic interaction Eur. J. Cancer 30A, 2039-2041. 

Niefh, C., Priebsch, A., Stege, A. and Lage, H. (2003) Modulation of the classical multidrug resistance (MDR) phenotype hy RNA interference (RNAi). FEBS Letters, 545, 144-150. 

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