Multidrug Resistance (MDR)

Introduction
Tumor cell resistance to cytotoxic drugs is considered one of the major obstacles to successful chemotherapy. Some tumors are initially resistant and never respond to cytostatic drug treatment; others initially respond well but eventually regrow and become resistant. This phenomenon may result from genetic mutations induced by the administered antitumor agent, or may represent the selection of preexisting resistant cell populations in the malignant tumor. Multidrug resistance (MDR) describes the simultaneous expression of cellular resistance to a variety of unrelated drugs primarily of natural origin.
There have been many excellent reviews  dealing with mechanisms of cellular drug resistance [1-27]. In addition to MDR-related proteins many other mechanisms of drug resistance have been documented in vitro. They are based on alterations in drug target enzymes and proteins, increased detoxification, alterations in cellular metabolism, enhanced ability to repair DNA damage, and failure to undergo apoptosis.
Proteins involved in MDR mechanisms are P-glycoprotein (Pgp), Multidrug Resistance-associated Proteins (MRPs), Major Vault Protein (MVP)/Lung Resistance-related Protein (LRP), and Breast Cancer Resistance Protein (BCRP).
Pgp and MRP belong to the ATP-binding cassette (ABC) superfamily of membrane transporter proteins [28, 29]. This superfamily comprises a broad range of proteins found in organisms from bacteria to humans, which transport a wide variety of substances such as ions, amino acids, sugars, peptides and proteins. For an excellent updated overview visit http://nutrigene.4t.com/humanabc.htm
 
P-glycoprotein [Pgp]
The classical form of MDR is mediated by P-glycoprotein (Pgp) that acts as a drug efflux pump. In humans, two closely related genes, MDR1 and MDR3, both located at the long arm of chromosome 7, encode highly homologous Pgp [30]. The expression of the MDR3 gene does not seem to be associated with drug resistance.
Pgp, the product of the MDR1 gene, is a 170kDa membrane protein which consists of two duplicated halves each containing six predicted hydrophobic membrane spanning segments followed by a highly conserved intracellular ATP-binding site [31]. Pgp detection has become an important tool in the investigation of MDR. A large panel of anti-human Pgp monoclonal antibodies has been developed, including MAbs that recognize internal (Clones: C219 (Prod. No. ALX-801-002), C494 (Prod. No. ALX-801-003), JSB-1 (Prod. No. ALX-801-004)) and external (Clones: MRK-16 (Prod. No. ALX-801-008), 4E3 (Prod. No. ALX-801-001) epitopes. These MAbs were used to study Pgp expression in MDR tumor cells but also in normal human tissues.
  
Multidrug Resistance-associated Proteins [MRPs]
Although increased levels of Pgp are likely to contribute to MDR in at least some tumor types, it has become evident that alternative, non-Pgp-mediated mechanisms of MDR exist.
The multidrug resistance-associated protein 1 (MRP1) has been identified by Cole and Deeley [32]. The MRP1 gene (ABCC1), located on chromosome 16p13.1, encodes a 1531-amino acid N-glycosylated integral membrane phosphoprotein, with a molecular weight of 190kDa. The amino acid identity between MRP1 and Pgp is only 15%, and the homology to chloride channel CFTR only 19%. Discovery of cMOAT/MRP2 (ABCC2) followed in 1996 [33-35]. Recently, by screening databases of human expressed sequence tags Kool, et al. identified three new homologs of MRP1, called MRP3 (ABCC3), MRP4 (ABCC4) and MRP5 (ABCC5) [36]. MRP6 (ABCC6) was added in 1998 [37] and the existence of a 7th family member, MRP7 (SIMRP7), has only been inferred from a database search. For excellent review articles see [8, 18]. 

Major Vault Protein [MVP]/Lung Resistance Protein [LRP]
Another protein related to MDR is the major vault protein (MVP)/lung resistance-related protein (LRP). This molecule was first discovered in a non-small cell lung cancer cell line selected for doxorubicin-resistance. It was detected by MAbs in a large panel of human tumor cell lines, all characterized by their MDR phenotype in the absence of Pgp overexpression [38]. The LRP gene was cloned and identified as the human major vault protein (MVP) [39]. For a recent review see [45] and [46].

Breast Cancer Resistance Protein [BCRP, MXR]
Recently a new multidrug resistance transporter has been identified and termed breast cancer resistance protein (BCRP/ABCG2) [40] and mitoxantrone-resistance half-transporter (MXR/ABCG2) [41]. BCRP has been described in ovarian, breast, colon and gastric cancer and fibrosarcoma cell lines. Cell lines overexpressing BCRP show resistance to mitoxantrone, flavopiridol, doxorubicin and daunorubicin, among others [42-44].