Pharmacologic circumvention of multidrug resistance

The ability of malignant cells to develop resistance to chemotherapeutic drugs is a major obstacle to the successful treatment of clinical tumors. The phenomenon multidrug resistance (MDR) in cancer cells results in cross-resistance to a broad range of structurally diverse antineoplastic agents, due to outward efflux of cytotoxic substrates by themdr1 gene product, P-glycoprotein (P-gp). Numerous pharmacologic agents have been identified which inhibit the efflux pump and modulate MDR. The biochemical, cellular and clinical pharmacology of agents used to circumvent MDR is analyzed in terms of their mechanism of action and potential clinical utility. MDR antagonists, termed chemosensitizers, may be grouped into several classes, and include calcium channel blockers, calmodulin antagonists, anthracycline andVinca alkaloid analogs, cyclosporines, dipyridamole, and other hydrophobic, cationic compounds. Structural features important for chemosensitizer activity have been identified, and a model for the interaction of these drugs with P-gp is proposed. Other possible cellular targets for the reversal of MDR are also discussed, such as protein kinase C. Strategies for the clinical modulation of MDR and trials combining chemosensitizers with chemotherapeutic drugs in humans are reviewed. Several novel approaches for the modulation of MDR are examined.Abbreviations ALL acute lymphocytic leukemia - AML acute myelogenous leukemia - CaM calmodulin - CsA cyclosporin A - MDR multidrug resistance - P-gp P-glycoprotein - PMA phorbol 12-myristate 13-acetate - PKC protein kinase C     

P-糖蛋白线粒体转位与线粒体DNA缺失肿瘤细胞多药耐药产生的关系

线粒体DNA缺失细胞(ρ~0细胞)拮抗化疗药物诱导的凋亡,但其确切机制尚不明确。本研究探讨P-gp线粒体转位与人肝癌细胞(SK-Hepl)mtDNA缺失细胞(ρ~0SK-Hep1)多药耐药产生的关系。以SK-Hep1、ρ~0SK-Hep1和转线粒体细胞SK-Hep1Cyb为研究对象,CCK-8方法检测细胞对药物敏感性;AnnexinV/PI双染法及DAPI染色法检测细胞凋亡;Westernblot检测P-gp表达;激光共聚焦显微镜结合免疫荧光检测P-gP细胞内分布。结果显示,SK-Hep1、ρ~0SK-Hep1和SK-Hep1Cyb细胞对多柔比星(DOX)的IC_(50)分别为0.62±0.02μg/ml、4.93±0.17μg/ml和0.57±0.02μg/ml。SK-Hep1、ρ~0SK-Hep1和SK-Hep1Cyb细胞凋亡率分别为1 1.25%±1.36%、4.75%±0.98%和14.50%±1.57%,ρ~0SK-Hep1对细胞凋亡有明显抗性。Western blot检测发现ρ~0细胞内P-gP、Bax、Bcl-2表达增加,Bcl-2/Bax比值增加。免疫荧光共定位显示,ρ~0细胞线粒体内P-gP...     

Different modalities of intercellular membrane exchanges mediate cell-to-cell p-glycoprotein transfers in MCF-7 breast cancer cells

Multi-drug resistance (MDR) is a phenomenon by which tumor cells exhibit resistance to a variety of chemically unrelated chemotherapeutic drugs. The classical form of multidrug resistance is connected to overexpression of membrane P-glycoprotein (P-gp), which acts as an energy dependent drug efflux pump. P-glycoprotein expression is known to be controlled by genetic and epigenetic mechanisms. Until now processes of P-gp gene up-regulation and resistant cell selection were considered sufficient to explain the emergence of MDR phenotype within a cell population. Recently, however, "non-genetic" acquisitions of MDR by cell-to-cell P-gp transfers have been pointed out. In the present study we show that intercellular transfers of functional P-gp occur by two different but complementary modalities through donor-recipient cells interactions in the absence of drug selection pressure. P-glycoprotein and drug efflux activity transfers were followed over 7 days by confocal microscopy and flow cytometry in drug-sensitive parental MCF-7 breast cancer cells co-cultured with P-gp overexpressing resistant variants. An early process of remote transfer was established based on the release and binding of P-gp-containing microparticles. Microparticle-mediated transfers were detected after only 4 h of incubation. We also identify an alternative mode of transfer by contact, consisting of cell-to-cell P-gp trafficking by tunneling nanotubes bridging neighboring cells. Our findings supply new mechanistic evidences for the extragenetic emergence of MDR in cancer cells and indicate that new treatment strategies designed to overcome MDR may include inhibition of both microparticles and Tunneling nanotube-mediated intercellular P-gp transfers.     

Molecular analysis of the multidrug transporter, P-glycoprotein

Inherent or acquired resistance of tumor cells to cytotoxic drugs represents a major limitation to the successful chemotherapeutic treatment of cancer. During the past three decades dramatic progress has been made in the understanding of the molecular basis of this phenomenon. Analyses of drug-selected tumor cells which exhibit simultaneous resistance to structurally unrelated anti-cancer drugs have led to the discovery of the human MDR1 gene product, P-glycoprotein, as one of the mechanisms responsible for multidrug resistance. Overexpression of this 170 kDa N-glycosylated plasma membrane protein in mammalian cells has been associated with ATP-dependent reduced drug accumulation, suggesting that P-glycoprotein may act as an energy-dependent drug efflux pump. P-glycoprotein consists of two highly homologous halves each of which contains a transmembrane domain and an ATP binding fold. This overall architecture is characteristic for members of the ATP-binding cassette or ABC superfamily of transporters. Cell biological, molecular genetic and biochemical approaches have been used for structure-function studies of P-glycoprotein and analysis of its mechanism of action. This review summarizes the current status of knowledge on the domain organization, topology and higher order structure of P-glycoprotein, the location of drug- and ATP binding sites within P-glycoprotein, its ATPase and drug transport activities, its possible functions as an ion channel, ATP channel and lipid transporter, its potential role in cholesterol biosynthesis, and the effects of phosphorylation on P-glycoprotein activity. This revised version was published online in August 2006 with corrections to the Cover Date.     

Multidrug resistance (MDR) genes in haematological malignancies

The emergence of drug resistant cells is one of the main obstacles for successful chemotherapeutic treatment of haematological malignancies. Most patients initially respond to chemotherapy at the time of first clinical admission, but often relapse and become refractory to further treatment not only to the drugs used in the first treatment but also to a variety of other drugs. Laboratory investigations have now provided a cellular basis for this clinical observation of multidrug resistance (MDR). Expression of a glycoprotein (referred to as P-glycoprotein) in the membrane of cells made resistantin vitro to naturally occurring anticancer agents like anthracyclines, Vinca alkaloids and epipodophyllotoxins, has been shown to be responsible for the so-called classical MDR phenotype. P-glycoprotein functions as an ATP-dependent, unidirectional drug efflux pump with a broad substrate specificity, that effectively maintains the intracellular cytotoxic drug concentrations under a non-cytotoxic threshold value. Extensive clinical studies have shown that P-glycoprotein is expressed on virtually all types of haematological malignancies, including acute and chronic leukaemias, multiple myelomas and malignant lymphomas. Since in model systems for P-glycoprotein-mediated MDR, drug resistance may be circumvented by the addition of non-cytotoxic agents that can inhibit the outward drug pump, clinical trials have been initiated to determine if such an approach will be feasible in a clinical situation. Preliminary results suggest that some haematological malignancies, among which are acute myelocytic leukaemia, multiple myeloma and non-Hodgkin's lymphoma, might benefit from the simultaneous administration of cytotoxic drugs and P-glycoprotein inhibitors. However, randomised clinical trials are needed to evaluate the use of such resistance modifiers in the clinic.Abbreviations ALL acute lymphocytic leukaemia - AML acute myelocytic leukaemia - BM bone marrow - CAT chloramphenicol acetyltransferase - CLL chronic lymphocytic leukaemia - CML chronic myelocytic leukaemia - CR complete remission - HCL hairy cell leukaemia - MDR multidrug resistance - MDS myelodysplastic syndrome - MM multiple myeloma - MoAb monoclonal antibody - NHL non-Hodgkin's lymphoma - PB peripheral blood - PCR polymerase chain reaction - PLL prolymphocytic leukaemia - RMA resistance modifying agent - VAD vincristine, doxorubicin, dexamethasone     

Changes in lipid and protein constituents of rafts and caveolae in multidrug resistant cancer cells and their functional consequences

The carcinogenic process involves a complex series of genetic and biochemical changes that enables transformed cells to proliferate, migrate to secondary sites and, in some cases, acquire mechanisms that make cancer cells resistant to chemotherapy. This phenomenon in its most common form is known as multidrug resistance (MDR). It is usually mediated by overexpression of P-glycoprotein (P-gp) or other plasma membrane ATPases that export cytotoxic drugs used in chemotherapy, thereby reducing their efficacy. However, additional adaptive changes are likely to be required in order to confer a full MDR phenotype. Recent studies have shown that acquisition of MDR is accompanied by up-regulation of lipids and proteins that constitute lipid rafts and caveolar membranes, notably glucosylceramide and caveolin. These changes may be related to the fact that in MDR cells a significant fraction of cellular P-gp is associated with caveolin-rich membrane domains, they may be involved in drug transport and they could have an impact on drug-induced apoptosis and on the phenotypic transformation of MDR cancer cells.     

Co-amplification of double minute chromosomes, multiple drug resistance, and cell surface P-glycoprotein in DNA-mediated transformants of mouse cells.

A genetic system comprised of mammalian cell mutants which demonstrate concomitant resistance to a number of unrelated drugs has been described previously. The resistance is due to reduced cell membrane permeability and is correlated with the presence of large amounts of a plasma membrane glycoprotein termed P-glycoprotein. This system could represent a model for multiple drug resistance which develops in cancer patients treated with chemotherapeutic drugs. We demonstrate here that the multiple drug resistance phenotype can be transferred to mouse cells with DNA from a drug-resistant mutant and then amplified quantitatively by culture in media containing increasing concentrations of drug. The amount of P-glycoprotein was correlated directly with the degree of drug resistance in the transformants and amplified transformants. In addition, the drug resistance and expression of P-glycoprotein of the transformants were unstable and associated quantitatively with the number of double minute chromosomes. We suggest that the gene for multiple drug resistance and P-glycoprotein is contained in these extrachromosomal particles and is amplified by increases in double minute chromosome number. The potential use of this system for manipulation of mammalian genes in general is discussed.     

The P-glycoprotein homologues of Plasmodium falciparum: Are they involved in chloroquine resistance?

Chloroquine has been the mainstay of antimalarial chemotherapy but the rapid spread of resistance to this important drug has now compromised its efficacy. The mechanism of chloroquine resistance has not been known but recent evidence from Plasmodium falciparum, the causative agent of the most severe form of human malaria, suggested similarities to the multidrug resistance phenotype (MDR) of mammalian tumour cells which is mediated by a protein molecule termed P-glycoprotein. Two mdr genes (pfmdr1 and pfmdr2) encoding P-glycoprotein homologues have been identified in P. falciparum and one of these (pfmdr1) has several alleles that have been linked to the chloroquine resistance phenotype. In contrast analysis of a genetic cross between chloroquine-resistant and -sensitive P. falciparum has suggested that the genes encoding the known P-glycoprotein homologues are not linked. This review outlines the similarities of the chloroquine resistance phenotype with the MDR phenotype of mammalian tumour cells and explores the possible role of the pfmdr genes.     

Changes in lipid and protein constituents of rafts and caveolae in multidrug resistant cancer cells and their functional consequences

The carcinogenic process involves a complex series of genetic and biochemical changes that enables transformed cells to proliferate, migrate to secondary sites and, in some cases, acquire mechanisms that make cancer cells resistant to chemotherapy. This phenomenon in its most common form is known as multidrug resistance (MDR). It is usually mediated by overexpression of P-glycoprotein (P-gp) or other plasma membrane ATPases that export cytotoxic drugs used in chemotherapy, thereby reducing their efficacy. However, additional adaptive changes are likely to be required in order to confer a full MDR phenotype. Recent studies have shown that acquisition of MDR is accompanied by upregulation of lipids and proteins that constitute lipid rafts and caveolar membranes, notably glucosylceramide and caveolin. These changes may be related to the fact that in MDR cells a significant fraction of cellular P-gp is associated with caveolin-rich membrane domains, they may be involved in drug transport and they could have an impact on drug-induced apoptosis and on the phenotypic transformation of MDR cancer cells.     

MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping

The human MDR3 gene is a member of the multidrug resistance (MDR) gene family. The MDR3 P-glycoprotein is a transmembrane protein that translocates phosphatidylcholine. The MDR1 P-glycoprotein related transports cytotoxic drugs. Its overexpression can make cells resistant to a variety of drugs. Attempts to show that MDR3 P-glycoprotein can cause MDR have been unsuccessful thus far. Here, we report an increased directional transport of several MDR1 P-glycoprotein substrates, such as digoxin, paclitaxel, and vinblastine, through polarized monolayers of MDR3-transfected cells. Transport of other good MDR1 P-glycoprotein substrates, including cyclosporin A and dexamethasone, was not detectably increased. MDR3 P-glycoprotein-dependent transport of a short-chain phosphatidylcholine analog and drugs was inhibited by several MDR reversal agents and other drugs, indicating an interaction between these compounds and MDR3 P-gp. Insect cell membranes from Sf9 cells overexpressing MDR3 showed specific MgATP binding and a vanadate-dependent, N-ethylmaleimide-sensitive nucleotide trapping activity, visualized by covalent binding with [alpha-(32)P]8-azido-ATP. Nucleotide trapping was (nearly) abolished by paclitaxel, vinblastine, and the MDR reversal agents verapamil, cyclosporin A, and PSC 833. We conclude that MDR3 P-glycoprotein can bind and transport a subset of MDR1 P-glycoprotein substrates. The rate of MDR3 P-glycoprotein-mediated transport is low for most drugs, explaining why this protein is not detectably involved in multidrug resistance. It remains possible, however, that drug binding to MDR3 P-glycoprotein could adversely affect phospholipid or toxin secretion under conditions of stress (e.g. in pregnant heterozygotes with one MDR3 null allele).     

Are altered pHi and membrane potential in hu MDR 1 transfectants sufficient to cause MDR protein-mediated multidrug resistance?

Multidrug resistance (MDR) mediated by overexpression of the MDR protein (P-glycoprotein) has been associated with intracellular alkalinization, membrane depolarization, and other cellular alterations. However, virtually all MDR cell lines studied in detail have been created via protocols that involve growth on chemotherapeutic drugs, which can alter cells in many ways. Thus it is not clear which phenotypic alterations are explicitly due to MDR protein overexpression alone. To more precisely define the MDR phenotype mediated by hu MDR 1 protein, we co-transfected hu MDR 1 cDNA and a neomycin resistance marker into LR73 Chinese hamster ovary fibroblasts and selected stable G418 (geneticin) resistant transfectants. Several clones expressing different levels of hu MDR 1 protein were isolated. Unlike previous work with hu MDR 1 transfectants, the clones were not further selected with, or maintained on, chemotherapeutic drugs. These clones were analyzed for chemotherapeutic drug resistance, intracellular pH (pHi), membrane electrical potential (Vm), and stability of MDR 1 protein overexpression. LR73/hu MDR 1 clones exhibit elevated pHi and are depolarized, consistent with previous work with LR73/mu MDR 1 transfectants (Luz, J.G. L.Y. Wei, S. Basu, and P.D. Roepe. 1994. Biochemistry. 33:7239-7249). The extent of these perturbations is related to the level of hu MDR 1 protein that is expressed. Cytotoxicity experiments with untransfected LR73 cells with elevated pHi due to manipulating percent CO2 show that the pHi perturbations in the MDR 1 clones can account for much of the measured drug resistance. Membrane depolarization in the absence of MDR protein expression is also found to confer mild drug resistance, and we find that the pHi and Vm changes can conceivably account for the altered drug accumulation measured for representative clones. These data indicate that the MDR phenotype unequivocally mediated by MDR 1 protein overexpression alone can be fully explained by the perturbations in Vm and pHi that accompany this overexpression. In addition, MDR mediated by MDR protein overexpression alone differs significantly from that observed for MDR cell lines expressing similar levels of MDR protein but also exposed to chemotherapeutic drugs.     

Analysis of the tangled relationships between P-glycoprotein-mediated multidrug resistance and the lipid phase of the cell membrane.

P-glycoprotein (Pgp), the so-called multidrug transporter, is a plasma membrane glycoprotein often involved in the resistance of cancer cells towards multiple anticancer agents in the multidrug-resistant (MDR) phenotype. It has long been recognized that the lipid phase of the plasma membrane plays an important role with respect to multidrug resistance and Pgp because: the compounds involved in the MDR phenotype are hydrophobic and diffuse passively through the membrane; Pgp domains involved in drug binding are located within the putative transmembrane segments; Pgp activity is highly sensitive to its lipid environment; and Pgp may be involved in lipid trafficking and metabolism. Unraveling the different roles played by the membrane lipid phase in MDR is relevant, not only to the evaluation of the precise role of Pgp, but also to the understanding of the mechanism of action and function of Pgp. With this aim, I review the data from different fields (cancer research, medicinal chemistry, membrane biophysics, pharmaceutical research) concerning drug-membrane, as well as Pgp-membrane, interactions. It is emphasized that the lipid phase of the membrane cannot be overlooked while investigating the MDR phenotype. Taking into account these aspects should be useful in the search of ways to obviate MDR and could also be relevant to the study of other multidrug transporters.     

What do proton motive force driven multidrug resistance transporters have in common?

The extensive progress of genome sequencing projects in recent years has demonstrated that multidrug resistance (MDR) transporters are widely spread among all domains of life. This indicates that they play crucial roles in the survival of organisms. Moreover, antibiotic and chemotherapeutic treatments have revealed that microorganisms and cancer cells may use MDR transporters to fight the cytotoxic action of drugs. Currently, several MDR extrusion systems are being investigated in detail. It is expected that understanding of the molecular basis of multidrug recognition and the transport mechanisms will allow a more rational design of new drugs which either will not be recognized and expelled by or will efficiently inhibit the activity of the MDR transporters. MDR transporters either utilize ATP hydrolysis or an ion motive force as an energy source to drive drugs out of the cell. This review summarizes the recent progress in the field of bacterial proton motive force driven MDR transporters.     

Effect of Stemona curtisii root extract on P-glycoprotein and MRP-1 function in multidrug-resistant cancer cells

Multidrug resistance (MDR) is the result of overexpression of membrane bound proteins that efflux chemotherapeutic drugs from the cells. Two proteins, P-glycoprotein (P-gp) and multidrug-resistance associated protein-1 (MRP-1) efflux chemotherapeutic agents out of the cancer cell that decrease intracellular drug accumulation, thereby decreasing the effectiveness of many chemotherapeutic agents. In the present study, the ethanolic extract of the roots of Stemona curtisii Hook. was tested for the potential ability to modulate the MDR phenotype and function of P-gp and MRP-1. The S. curtisii extract reversed the resistance to putative chemotherapeutic agents, including vinblastine, paclitaxel and colchicine of KB-V1 cells (MDR human cervical carcinoma with high P-gp expression) in a dose-dependent manner, but not in KB-3-1 cells (drug sensitive human cervical carcinoma, which lack P-gp expression). The root extract also increased the intracellular uptake and retention of (3)[H]-vinblastine in KB-V1 cells dose dependently. The extract did not influence MDR phenotype-mediated MRP-1 in MRP1-HEK293 (human embryonic kidney cells stably transfected with pcDNA3.1-MRP1-H10 which show high MRP-1 expression) and pcDNA3.1-HEK293 (wild type). In summary, the S. curtisii root extract modulated P-gp activity but not MRP-1 activity. The result obtained from this study strongly indicated that S. curtisii extract may play an important role as a P-gp modulator as used in vitro and may be effective in the treatment of multidrug-resistant cancers. The purified form of the active components of S. curtisii extract should be investigated in more details in order to explain the molecular mechanisms involved in P-gp modulation. This is the first report of new biological activity in this plant, which could be a potential source of a new chemosensitizer.     

Multiple Drug Resistance Mechanisms in Cancer

Multiple drug resistance (multidrug resistance; MDR), a phenomenon whereby human tumours that acquire resistance to one type of therapy are found to be resistant to several other drugs that are often quite different in both structure and mode of action, has been recognised clinically for several decades. An important advance in our understanding of MDR came with the identification of P-glycoprotein and other related transporters that were expressed in some cancer cells and could recognise and catalyse the efflux of diverse anticancer drugs from cells. A second advance came from an understanding of the mechanism of programmed cell death or apoptosis, leading to MDR mediated by increased to resistance to anticancer drug-induced apoptosis. A third advance came with the finding that the proliferation of human tumours was driven by a small population of self-renewing tumour cells, focussing attention on the MDR properties of these so-called tumour stem cells rather than on the cells that comprised the majority of the tumour population. A fourth advance was the delineation of features of the tumour microenvironment, including immunosuppression, which essentially provided tumour stem cells with an MDR phenotype. Most published work on the overcoming of MDR has concentrated on inhibition of drug transporters but the complexity of mechanisms contributing demands a broad strategy for the development of methods to overcome MDR in a clinical setting.     

Transepithelial transport of drugs by the multidrug transporter in cultured Madin-Darby canine kidney cell epithelia

We studied transepithelial transport of 3H-labeled hydrophobic cationic drugs in epithelia formed by wild-type and by drug-resistant Madin-Darby canine kidney (MDCk) cells that had been infected with a retrovirus carrying the multidrug-resistance (MDR1) cDNA which encodes the P-glycoprotein. P-glycoprotein is an ATP consuming plasma membrane multidrug transporter responsible for the efflux of cytotoxic chemotherapeutic drugs from resistant cancer cells. Wild-type MDCK cells have small amounts of P-glycoprotein detected by immunoprecipitation. Net transepithelial transport across wild-type MDCK epithelia was demonstrated. Basal to apical flux of 100 nM vinblastine was about six times higher than apical to basal flux. Addition of unlabeled vinblastine reduced basal to apical flux of tracer and increased apical to basal flux of tracer, a pattern expected if there is a saturable pump that extrudes vinblastine at the apical plasma membrane. Daunomycin, vincristine, and actinomycin D were also actively transported and at 20 microM these agents inhibited transport of vinblastine, suggesting that wild-type MDCK cells have a common transporter for all these drugs. Vinblastine transport was also inhibited by 20 microM verapamil, which inhibits the multidrug transporter and reverses multidrug-resistance in non-polarized cells. Net transepithelial transport of all these cytotoxic drugs and of verapamil was much higher in epithelia formed by MDCK cells infected with a human MDR1 virus (MDR-MDCK) which is expressed on the apical surface of MDR-MDCK monolayers. Because the transport of these cytotoxic drugs and verapamil is increased in MDR-MDCK epithelia compared to wild-type MDCK epithelia, transport in both these cell populations can be attributed to P-glycoprotein. These results are consistent with a role for P-glycoprotein in multidrug secretory transport across the epithelium of the proximal tubule since P-glycoprotein is normally expressed on the apical membrane of proximal tubule cells.     

Tetrandrine and fangchinoline,bisbenzylisoquinoline alkaloids from Stephania tetrandra can reverse multidrug resistance by inhibiting P-glycoprotein activity in multidrug resistant human cancer cells

The overexpression of ABC transporters is a common reason for multidrug resistance (MDR) in cancer cells. In this study, we found that the isoquinoline alkaloids tetrandrine and fangchinoline from Stephania tetrandra showed a significant synergistic cytotoxic effect in MDR Caco-2 and CEM/ADR5000 cancer cells in combination with doxorubicin, a common cancer chemotherapeutic agent. Furthermore, tetrandrine and fangchinoline increased the intracellular accumulation of the fluorescent P-glycoprotein (P-gp) substrate rhodamine 123 (Rho123) and inhibited its efflux in Caco-2 and CEM/ADR5000 cells. In addition, tetrandrine and fangchinoline significantly reduced P-gp expression in a concentration-dependent manner. These results suggest that tetrandrine and fangchinoline can reverse MDR by increasing the intracellular concentration of anticancer drugs, and thus they could serve as a lead for developing new drugs to overcome P-gp mediated drug resistance in clinic cancer therapy.     

Genes of multidrug resistance in haematological malignancies

Since the early 1970s, multiple drug resistance has been known to exist in cancer cells and is thought to be attributable to a membrane-bound, energy-dependent pump protein (P-glycoprotein [P-gp]) capable of extruding various related and unrelated chemotherapeutic drugs. The development of refractory disease in haematological malignancies is frequently associated with the expression of one or several multidrug resistance (MDR) genes. MDR1, multidrug resistance-associated protein (MRP) and lung-resistance protein (LRP) have been identified as important adverse prognostic factors. Recently it has become possible to reverse clinical MDR by blocking P-gp-mediated drug efflux. The potential relevance of these reversal agents of MDR as well as the potential new approaches to treat the refractory disease are discussed in this article. In addition, an array of different molecules and mechanisms by which resistant cells can escape the cytotoxic effect of anticancer drugs has now been identified. These molecules and mechanisms include apoptosis-related proteins and drug inactivation enzymes. Resistance to chemotherapy is believed to cause treatment failure in more than 50% patients. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanism of drug resistance in haematological malignancies with emphasis on molecules involved in MDR. In addition, it brings the survey of methods involved in determination of MDR, in particular P-gp/MDR1, MRP and LRP.