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PubMed1995

[The clinical significance of the expression of the multiple-drug resistance protein P-glycoprotein in chronic myeloleukemia].

Cell resistance to pharmaceutical agents arises among other causes because of multiple drug resistance induced by P-glycoprotein (P-gp). The analysis of expression of P-gp and differentiation antigens of hemopoietic cells has been made on myeloid cells from 14 patients in CML chronic phase and 25 with CML acceleration and in blast crisis. Surface antigen expression was evaluated at flow cytofluorimetry (FACScan unit). Fluorescent dye rodomin (Rh123) helped examine P-gp functional activity. A close relationship is shown between P-gp expression and CD34 (r = 0.69. p = 0.0004), this giving evidence of these antigens expression on the same cells. In chronic phase P-gp is expressed on a few cells in some patients, its activity being low or absent. The appearance of UIC-2+ cells was unrelated to previous chemotherapy and brought no resistance to treatment. In terminal stage P-gp is expressed in 50% of cases. Functional tests identified the active protein in blast populations with a large number of UIC-2+ cells and in some patients with a small number of cells expressing P-gp. Therefore, comprehensive clinical investigations are needed of multiple drug resistance, though in half of the resistant patients in AML blast crisis P-gp+ cells were not identified suggesting the existence of other mechanisms responsible for resistance to treatment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Multiple drug resistance parameter expression in ovarian cancer.

OBJECTIVE: Drug resistance represents a complex problem for the treatment of ovarian cancer. This study was undertaken to assess several putative resistance parameters (DRP) in parallel in cancer tissue from newly diagnosed patients with ovarian cancer in order to establish possible correlations to known clinical factors and prognosis. MATERIAL AND METHODS: Tumor and adjacent tumor free ovarian tissue samples from 39 consecutive, untreated female patients with ovarian cancer were obtained and as potential DRPs, the level of glutathione (GSH), the activities of glutathione S-transferase (GST), glutathione-peroxidase (GPx), O6-alkylguanine-DNA alkyltransferase (Atase), and topoisomerase II (TOPO) were assessed biochemically, and P-glycoprotein (Pgp) was assessed by Western blotting. RESULTS: Interindividual variations were high and each patient exhibited an individual profile of resistance factor expression. Levels of GSH were increased with stage (linear trend: P < 0.002), and GST, GPx, and Atase showed a similar tendency. With few exceptions no correlation was found between the DRPs and other prognostic characteristics. All tested DRPs except Pgp showed significantly higher levels/activities in tumor tissues than in the surrounding tumor free tissues (P < 0.05). The tested DRPs were found not to influence response to treatment. CONCLUSIONS: It is concluded that elevated DRPs reflect an intrinsic pattern of components of the detoxifying system in the tumor tissue. This pattern differs between patients and may partly explain the difficulty to assess the clinical importance of individual DRPs in order to translate them into recommendations for specific therapies.

Adult↗
PubMed2002

The impact of multiple drug resistance (MDR) proteins on chemotherapy and drug discovery.

Transportation of molecules across the cell membrane in living organisms is a critical aspect of life. Transportation includes importation of nutrients from the environment and exportation of toxic compounds. When export includes therapeutic compounds, then the practice of clinical medicine may become compromised. Often efflux of therapeutic compounds is mediated by a large superfamily of proteins referred to as multidrug resistance (MDR) proteins. The initial sections of this chapter are focused on MDR proteins and their negative impact on clinical medicine in cancer chemotherapy as well as infectious diseases mediated by bacteria, fungi and parasites. A brief description of major classes of MDR proteins found in microbes is followed by a more exhaustive treatment of ABC transporters in lower eukaryotes and parasites as well as cancerous mammalian cells. Later sections deal with potential and real positive aspects and applications brought about by a growing knowledge of MDR proteins. Examples described include improved antibiotic production, leveraging MDR proteins in drug discovery, new therapeutic options, dual therapy in treatment of cancer and infectious diseases, and finally MDR proteins as targets for new classes of therapeutic compounds.

Animals↗
PubMed2006

Mechanisms and strategies to overcome multiple drug resistance in cancer.

One of the major problems in chemotherapy is multidrug resistance (MDR) against anticancer drugs. ATP-binding cassette (ABC) transporters are a family of proteins that mediate MDR via ATP-dependent drug efflux pumps. Many MDR inhibitors have been identified, but none of them have been proven clinically useful without side effects. Efforts continue to discover not toxic MDR inhibitors which lack pharmacokinetic interactions with anticancer drugs. Novel approaches have also been designed to inhibit or circumvent MDR. In this review, the structure and function of ABC transporters and development of MDR inhibitors are described briefly including various approaches to suppress MDR mechanisms.

ATP-Binding Cassette Transporters↗
PubMed2001

Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists.

A significant problem in the clinical treatment of cancer relates to the development of tumor resistance to many chemotherapeutic agents. Acquired drug resistance is often mediated through overexpression of membrane transport proteins that effectively efflux anticancer agents. Two of the best-studied transporters, P-glycoprotein (Pgp) and MRP1, have pharmacological properties that only partially overlap. In our search for improved drug-resistance antagonists, we have identified a family of substituted quinoxalines that selectively antagonizes Pgp over MRP1. Consequently, a focused library of congeners was designed and synthesized starting with a parent bromomethylquinoxalinone. This parent quinoxalinone was then condensed with a series of phenols to yield a family of substituted phenoxymethylquinoxalinones. These compounds were evaluated for their toxicity toward drug-sensitive MCF-7 breast carcinoma cells and for their abilities to antagonize Pgp and MRP1 in drug-resistant cell lines (NCI/ADR and MCF-7/VP, respectively). The results of this structure-activity study indicate that compounds with carbonyl substitutions of the phenoxy group (ester, amide, or ketone moieties) demonstrate excellent antagonism of Pgp while having relatively low toxicity toward drug-sensitive cells. Importantly, none of these compounds antagonized MRP1. Because of their transporter selectivity, we predict that substituted quinoxalinones may be more effective MDR modulators in vivo than are nonselective transporter antagonists.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Reversal of multiple drug resistance in cholangiocarcinoma by the glutathione S-transferase-pi-specific inhibitor O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-D-phenylglycine ethylester.

Cholangiocarcinoma is markedly resistant to chemotherapy and has a dismal prognosis, but its mechanism of drug resistance is unknown. This study examines whether glutathione S-transferase-pi (GSTP1-1) is involved in resistance to anticancer drugs in cholangiocarcinoma and whether GSTP1-1-specific inhibitors can overcome this resistance. First, immunohistochemical examination disclosed strong staining of all our 17 cholangiocarcinoma specimens for GSTP1-1, irrespective of histological type. Transfection of the GSTP1-1 antisense expression vector into a human cholangiocarcinoma cell line (HuCCT1) apparently decreased its intracellular GSTP1-1 concentration, and the sensitivity of transfectants to adriamycin (ADR), cisplatin, and alkylating agents such as melphalan and 4-hydroxyperoxycyclophosphamide (4-HC) was increased significantly, compared with that of mock transfectants. We next synthesized GSTP1-1-specific inhibitors by elongating the carbon chain of the ethylester at the N-terminal of gamma-glutamyl-S-benzylcysteinyl-phenylglycyl diethylester and performed a pharmacokinetic study on them. Of six GSTP1-1 inhibitors tested, O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-d-phenylglycine ethylester (C16C2) showed the smallest volume of central compartment and smallest volume of distribution at steady state and the second smallest clearance, being the most effective inhibitor in vivo. The IC50 value of ADR or 4-HC for HuCCT1 cells decreased greater by treatment with C16C2 in a dose-dependent manner, paralleling the decrease in GSTP1-1 activity, than that of ADR or 4-HC alone. The antitumor activity of ADR or cyclophosphamide was clearly enhanced by combination therapy with C16C2 in a xenograft model. In conclusion, our results demonstrated that GSTP1-1 is a resistance factor for anticancer drugs in cholangiocarcinoma and that C16C2, a GSTP1-1-specific inhibitor, is a potent agent against the resistance.

Animals↗
PubMed1999

[Modulation of multiple drug resistance by nomegestrol acetate and droloxifene in K562/A02].

OBJECTIVE: To study the modulation of mdr1, glutathione S-transferase Pi (GST pi), topoisomerase II alpha (Topo II alpha) and multidrug resistance-associated protein (MRP) by nomegestrol acetate (NOM) and droloxifene (DRO) in K562 cell line. METHODS: Adriamycin (ADM)-resistant K562 (K562/A02) and parental K562 cells were treated with NOM and DRO. The alterations of chemosensitivity to ADM were evaluated by MTT assay, mRNA and protein expression of drug-resistant gene by RT-PCR and immunohistochemistry and accumulation of ADM by flow cytometry (FCM). RESULTS: Both NOM and DRO markedly enhanced chemosensitivity to ADM of K562/A02 cells. After 20, 10 and 5 mumol/L of NOM or DRO treatment, the chemosensitivities to ADM were increased by 17.7, 15.1 and 5.1 times, respectively in NOM treated cells and by 12.3, 12.9 and 4.0 times, respectively in DRO treated cells. In both the drugs treated cells the accumulation of ADM was increased by 2-3 times. The MDR reversal activity of NOM was similar to that of VRP, but the modulatory action of DRO on K562/A02 cells was weaker than that of VRP at concentration of 20 mumol/L. After 20 mumol/L of NOM treatment, chemosensitivity to ADM of K562 cells was markedly enhanced (P < 0.05). Both NOM and DRO were found to significantly inhibit mdr1 and GST pi expression and increase Topo II alpha expression at the mRNA and protein level. This modulation of gene expression was time dependent and the maximal effects appeared 5 days after drugs treatment. Both NOM and DRO failed to modulate the MRP expression. In K562 cells, NOM and DRO also inhibited GST pi expression (P < 0.05). CONCLUSION: Both NOM and DRO could markedly reverse the MDR of K562/A02 cells. The reversal activity of NOM was comparable to that of VRP. Both the drugs could modulate mdr1, GST pi and Topo II alpha expression in a time dependent manner.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Multiple drug resistance phenotype of human endothelial cells induced by vascular endothelial growth factor 165.

AIM: To investigate the effect of vascular endothelial growth factor 165 (VEGF165) on sensitivity of endothelial cells to anticancer drugs. METHODS: Human dermal microvessel endothelial cells (HDMEC) were incubated with anticancer drugs in the presence of VEGF165. Survival of endothelial cells was assayed by MTT method. DNA fragments of apoptosis were detected by agarose electrophoresis. Potential mechanisms underlying the effect of VEGF165 on endothelial cells were investigated with RT-PCR and Western blot analysis. RESULTS: VEGF165 induced the multidrug resistance phenotype of HDMEC to a wide variety of anticancer drugs such as epirubicin, cisplatin, etoposide, mytomycin C, vincristine, CPT-11, and taxol in vitro. This protective effect was partly due to the up-regulation of lung drug resistance protein (LRP) and multidrug resistance-associated protein (MRP), as well as the down-regulation of Bax protein induced by VEGF165. CONCLUSION: VEGF165 induced multidrug resistance phenotype of endothelial cells, which implicated the anti-angiogenic effect of anticancer drugs might depend on microenvironment of tumors in vivo.

Angiogenesis Inhibitors↗
PubMed1994

[The isolation and genetic characteristics of the new cell line of mouse myeloma spEBR-5 selected for ethidium bromide resistance and characterized by multiple drug resistance].

Stable mutant cells spEBR-5, resistant to ethidium bromide in concentration of 5 micrograms/ml, have been isolated by multistep selection in mouse myeloma cells sp2/0-Ag14. The spEBR-5 cells, selected with ethidium bromide, appeared to be cross resistant to unrelated drugs in connection with mdr/lb gene amplification and overexpression. Five specific chromosomal markers were detected in the karyotype of spEBR-5 cells as a result of chromosome structural rearrangement. No cytological manifestation of gene amplification such as HCR of chromosomes or DMs was found. A diffuse location of amplified sequences in chromosome(s) is suggested. The new mutant cell lines spEBR-5 can be used as a model for investigation of multidrug resistance mechanisms.

Animals↗
PubMed1995

[Relationship between amplicon composition and cytologic type of structures containing amplified DNA in murine P388 cells with multiple drug resistance].

Previously, we showed that, development of multidrug resistance (MDR) in mouse P388 leukemia cells, is often associated with the appearance of newly-formed chromosome-like structures that contain amplified copies of the mdrl gene. In the present study, we compared amplicon content in P388 sublines showing different types of these structures. A strong correlation between the formation of specific acentric markers consisting of two identical arms and the absence of the sorcin gene co-amplification was found. In all the sublines containing other types of chromosome-like structures, the sorcin gene is co-amplified.

Animals↗
PubMed1996

[MDR (Multiple Drug Resistant) type of resistance to chemotherapy in clinical practice].

Multifactorial resistance is the main mechanism of chemotherapy failure in cancers. Multidrug resistance (MDR) is related to the expression of a 170 kDa membrane glycoprotein, the so-called P-glycoprotein (P-gp). This protein is able to extrude drugs of various structures and mechanisms out of the cytoplasm. P-gp is a pronostic value in hemopathy as well as in child sarcoma, osteosarcoma and neuroblastoma. Modulator agents of different generations are capable of inhibiting P-gp. MDR modulation is obtained in hemopathies and is associated with an eradication of the P-gp (+) cell clones. In solid tumors, clinical trials using verapamil or cyclosporin are not so convincing. It is likely that other mechanisms of resistance are responsible for tumor progression, such as the MRP system, glutathion and topoisomerases. A better knowledge of multifactorial resistance and drug synthesis counteracting these resistance mechanisms will allow to elaborate new therapeutic basis for cancer therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

[Effect of quinine on the multiple drug resistance and intracellular distribution of pirarubicin in LR73 tumor cells: a comparative study with verapamil and S9788 by confocal laser microspectrofluorometry].

Effectiveness of chemotherapeutic treatment is limited by multidrug resistance (MDR) phenomenon mediated by the overexpression of P-glycoprotein 170 termed Pgp which serves as an efflux pump removing several types of cytostatic drugs from the MDR cells. Several small molecules, frequently lipophilic cations and weak bases, are able to reverse in vitro this resistance. Several studies have shown that MDR modulators interact with Pgp. However, some molecules do not interact with Pgp but are able to completely restore drug sensitivity (e.g., quinine). Bennis et al. (1995) have shown recently that in contrast to verapamil and S9788, quinine increases nuclear doxorubicin accumulation without modifying its intracellular concentration. From this work, the authors concluded that quinine has essentially intracellular targets involved in drug distribution (cytoplasm to nucleus) from sequestration compartments. Their results have been obtained using spectrofluorometry on cell populations and fluorescence microscopy. By using confocal laser microspectrofluorometry, we investigated restoration of nuclear THP-DOX accumulation and sensitivity by verapamil, S9788 and quinine in 2 variants of the Chinese hamster ovary cells LR73, selected for resistance to doxorubicin (LR73D) and transfected with the mdr1 gene (LR73R), as well as in the sensitive ones (LR73S). Results show that verapamil and S9788 were able to restore THP-DOX sensitivity in resistant cells by increasing nuclear THP-DOX accumulation. This restoration is the consequence of Pgp inhibition and redistribution of the anticancer drug from the cytoplasm to nucleus. Quinine, in contrast, restores the sensitivity of MDR cells to THP-DOX and decreased their resistance index, but has no effect on THP-DOX nuclear accumulation. This suggests that quinine modifies the molecular environment of anthracyclines and/or their binding to cytoplasmic targets involved in another mechanism of anthracycline action.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

[Reorganization of elements of the cytoskeletal and vacuolar systems in tumor cells in the early stage of developing multiple drug resistance].

The multidrug resistance (MDR) is one of the main reasons for chemotherapeutic failures in cancer patients. The overexpression of MDR gene product (Pgp) leads to the appearance of resistant tumor cells. We investigated alterations of cell structures in cells with a low level MDR and Pgp expression. The Syrian hamster embryo fibroblasts transformed by the Raus sarcoma virus were used in our experiments. Resistant sublines were isolated by propagation of the cells in colchicine supplemented medium. We have found that the first steps of MDR are accompanied by significant alterations of cytoskeleton elements and vacuolar system, e.g. changes in actin stress-fibres organization, microtubule distribution, the Golgi complex structure, vesicular transport. We suppose that the above cell structural alterations are not accidental. Perhaps, they are also essential for evolution of multidrug resistant mechanisms.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Short report: association between chloroquine and amodiaquine resistance and allelic variation in the Plasmodium falciparum multiple drug resistance 1 gene and the chloroquine resistance transporter gene in isolates from the upper Nile in southern Sudan.

Amodiaquine, a 4-aminoquinoline compound, is being considered as an alternative to chloroquine and pyrimethamine/sulfadoxine where resistance in Plasmodium falciparum to both drugs has been selected. Although amodiaquine is more potent than chloroquine, its effectiveness is reduced in areas where chloroquine resistance is high. We report an association of the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multiple drug resistance 1 (pfmdr1) gene, two chloroquine resistance markers, with chloroquine and amodiaquine efficacy in vivo in southern Sudan. The data show that the allele of the pfcrt gene with a lysine to threonine change at codon 76 is strongly associated with both chloroquine and amodiaquine resistance. No such association was observed with the pfmdr1 gene.

ATP-Binding Cassette Transporters↗
PubMed2002

Tissue distribution and chemical induction of multiple drug resistance genes in rats.

Multiple drug resistance (mdr) genes encode P-glycoprotein, which is responsible for resistance to some cancer chemotherapeutic drugs and efflux of xenobiotics of cells. Thus, mdr can protect organs from xenobiotics. In rats, there are two mdr1 genes capable of xenobiotic transport, mdr1a and mdr1b. The purpose of this study was to determine the tissue distribution of rat mdr1a and mdr1b mRNA and whether microsomal enzyme inducers that increase phase I and II drug-metabolizing enzymes coordinately regulate mdr1a and/or mdr1b. The mRNA levels of mdr1a and mdr1b were determined using branched-DNA signal amplification technology. The highest level of expression of mdr1a mRNA was observed in the gastrointestinal tract, with levels increasing, respectively, from duodenum, jejunum, and ileum to large intestine. Expression levels of mdr1a mRNA in the cerebral cortex, cerebellum, kidney, lung, and liver were less than one-tenth of that in the ileum. The tissue distribution of mdr1b mRNA was similar to mdr1a with highest expression in the gastrointestinal tract but only about 3-fold higher than in most other tissues. The induction of mdr1a and mdr1b mRNA transcripts in liver, kidney, and ileum by treatment of rats with 18 chemicals representing aryl hydrocarbon receptor ligands, constitutive androstane receptor ligands, pregnane X receptor ligands, peroxisome proliferator-activated receptor ligands, electrophile-response-element activators, and CYP4502E1 inducers was assessed. Hepatic, renal, and intestinal expression of mdr1a and mdr1b mRNA were not significantly altered by treatment of rats with any of these classes of ligands. In conclusion, the primary expression of rat mdr1 genes is in the gastrointestinal tract where they are thought to function to decrease the absorption of some xenobiotics. Rat mdr1 gene expression is not readily increased by microsomal enzyme inducers in rats through coordinate mechanisms with phase I and II drug-metabolizing enzymes.

ATP Binding Cassette Transporter, Subfamily B↗