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At least 19 recordsLinked to original sources
PubMed1995

Selection and characterization of verapamil-resistant multidrug resistant cells.

Multidrug resistant cells may become acutely sensitive to the calcium channel blocker verapamil, in spite of the fact that its accumulation by these cells is negligible. We selected verapamil-resistant mutants from multidrug resistant Chinese hamster ovary cells. Levels of P-glycoprotein expression and cross-resistance profiles remained unaltered in the verapamil-resistant multidrug resistant cells. As well, a photoactive verapamil analog specifically bound to P-glycoprotein in these cells. We had previously used a photoactive anthracycline to show that calcium antagonists and several anticancer drugs bind to P-glycoprotein at overlapping or interacting sites. Verapamil and its analogues no longer inhibit the binding of either anticancer drugs or calcium channel blockers to P-glycoprotein. Sequencing of P-glycoprotein revealed that no change had occurred in the coding sequence as a result of the selection procedure.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1986

Multidrug resistance.

Multidrug resistance describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. This phenotype occurs frequently in mammalian cell lines and transplantable tumours selected for resistance to a single drug. Reduced cellular accumulation of the drugs involved appears to account for the resistance. This may be a consequence of reduced drug influx, increased drug efflux, or both. A wide variety of biochemical changes have been identified in multidrug resistant cell lines, the most consistent of which is the increased expression of P-glycoprotein, a conserved, high molecular weight, plasma membrane glycoprotein. The level of P-glycoprotein expression correlates with the degree of drug resistance in a variety of different cell types. In a number of multidrug resistant cell lines, overexpression of P-glycoprotein results from gene amplification. While the function of P-glycoprotein is unknown, independent lines of evidence support the notion that P-glycoprotein is the causative molecule mediating the multidrug resistance phenotype. Significant levels of P-glycoprotein expression have been detected in some biopsy specimens from patients with ovarian and sarcoma tumours. These findings suggest that multidrug resistant tumour cells can occur in human malignancies. The presence of such cells may affect the outcome of chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1986

Chromosome-mediated gene transfer of multidrug resistance.

Multidrug resistance can be transferred from drug-resistant LZ Chinese hamster cells to drug-susceptible mouse LTA cells by chromosome-mediated gene transfer. Analysis of genomic DNA demonstrated the transfer of multiple copies of a DNA domain which is amplified in the donor multidrug-resistant cells. The transfer of 10 to 15 copies of the Chinese hamster gene was sufficient to produce a multidrug-resistant phenotype. Chromosome transferents exhibited overexpression of an mRNA of approximately 5 kilobases which has previously been demonstrated to be encoded by the amplified DNA domain of the donor LZ cells. Phenotypic analysis of individual clones selected in adriamycin showed the resistance to be pleiotropic. All clones tested demonstrated similar levels of cross-resistance to the drugs daunorubicin and colchicine. These results indicate that the DNA sequences transferred confer the complete multidrug-resistant phenotype on recipient cells and suggest that multidrug resistance is due to overexpression of the protein encoded by the 5-kilobase mRNA.

Animals↗
PubMed1994

The protein kinase C inhibitor CGP 41251, a staurosporine derivative with antitumor activity, reverses multidrug resistance.

Multidrug resistance (MDR) is frequently associated with overexpression of a 170-kDa P-glycoprotein (Pgp). Data suggest altered protein kinase C (PKC) activity in cells expressing the multidrug-resistant phenotype. The staurosporine derivative CGP 41251, an experimental anticancer drug, has been shown to exert selectivity for inhibition of protein kinase C activity and to exhibit antitumor activity in vitro and in vivo. Here we show that CGP 41251 is also able to reverse MDR. After treatment of the multidrug-resistant human lymphoblastoid cell line CCRF-VCR1000 with 500 nM Adriamycin, cell proliferation was reduced to 81% of untreated controls. A combination of 500 nM Adriamycin with a non-toxic concentration of 150 nM CGP 41251 (IC50 for inhibition of cell proliferation 420 nM CGP 41251) inhibits cell proliferation of CCRF-VCR1000 cells to 29% of untreated controls. In sensitive CCRF-CEM cells no enhancement of Adriamycin-induced cytotoxicity was observed upon addition of 150 nM CGP 41251. Strong synergism of the inhibition of cell proliferation was also observed after concomitant treatment of KB-8511 cells with CGP 41251 and Vinblastine or Adriamycin. Drug-sensitive KB-31 cells could not be further sensitized to Adriamycin or Vinblastine with CGP 41251 doses above 100 nM. Pretreatment with 50-1000 nM CGP 41251 for 30 min led to a dose-dependent increase in the intracellular accumulation of rhodamine 123, a substrate of P-glycoprotein. Treatment of multidrug-resistant CCRF-VCR1000 cells with CGP 41251 for 10 min was sufficient to inhibit the efflux of rhodamine 123. Preincubation with CGP 41251 for 12 or 24 hr did not alter multidrug resistance gene (mdrI)-mRNA levels. CGP 41251, a drug with antitumor efficacy in experimental systems, might offer an attractive combination partner for the treatment of tumors expressing the MDR phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Evidence for impaired mitoxantrone and vinblastine binding in P388 murine leukemia cells with multidrug resistance.

Multidrug resistance is associated with a P170 glycoprotein efflux pump that limits net drug accumulation in resistant cell lines. Other evidence has suggested that diminished net drug uptake in multidrug resistant (MDR) cells is due to decreased drug binding as well. To assess the contribution of binding differences to net drug accumulation and retention in MDR cells, mitoxantrone and vinblastine, two agents commonly associated with the MDR phenotype but with different mechanisms of action and intracellular binding sites, were studied in P388 murine leukemia cells. For both drugs, resistance was associated with a marked reduction in tightly bound drug which can account for the diminished net drug accumulation in this cell line; even at 1 microM vinblastine when the exchangeable component was one-half that of the sensitive cells, the nonexchangeable component was only one-seventh. For mitoxantrone, the exchangeable drug component was greater in resistant cells at low drug levels (1 microM) and similar at high drug levels (10 microM). For vinblastine, the exchangeable drug component was decreased in the resistant cells at 1 microM, but the difference compared to sensitive cells became neglible at 10 microM. The data indicate that diminished net drug uptake in the P388 MDR cell line was associated with a marked decrease in tightly bound, i.e. nonexchangeable, drug fractions for both mitoxantrone and vinblastine. Therefore, alterations in intracellular binding are in important factor in the decreased cellular uptake and retention of drugs in the multidrug resistance phenomenon. The relationship between these changes and the P170 efflux pump requires further clarification.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

P-glycoproteins: mediators of multidrug resistance.

Multidrug resistance represents a major obstacle to successful chemotherapy of metastatic disease. Elevated levels in cancer cells of the product of the multidrug resistance gene, P-glycoprotein or the multidrug transporter, have been associated with the development of simultaneous resistance to a great variety of amphiphilic cytotoxic drugs. P-glycoprotein is an integral plasma membrane protein which contains 12 putative transmembrane regions and two ATP binding sites. It confers multidrug resistance by functioning as an energy-dependent drug efflux pump. Here we describe recent studies on the biosynthesis, structure, function, and mechanism of action of P-glycoprotein which have provided insights into the complexity of this multifunctional transport system and revealed an additional chloride channel activity. The physiological role of P-glycoprotein, however, still remains to be elucidated.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Monoclonal antibody MRK16 reverses the multidrug resistance of multidrug-resistant transgenic mice.

Using multidrug-resistant (MDR)-transgenic mice, whose bone marrow cells express the human MDR1 gene at a level approximately equal to that found in many human cancers, we determined the efficacy of human-specific anti-P-glycoprotein monoclonal antibody MRK16 in overcoming multidrug resistance in an intact animal. MRK16 alone (2 mg) did not significantly affect the WBC counts of the MDR-transgenic mice, but MRK16, as well as the F(ab')2 fragments of MRK16, led to a dose-dependent circumvention of bone marrow resistance against daunomycin, doxorubicin, vincristine, vinblastine, etoposide, and taxol. This sensitizing effect could not be enhanced by combining MRK16 with low molecular weight chemosensitizing agents such as verapamil, quinine, quinidine, or cyclosporin A. We also investigated the concept of specifically targeting and killing multidrug-resistant cells by using MRK16 coupled to Pseudomonas exotoxin (PE). MRK16-PE resulted in a dose-dependent killing of bone marrow cells in MDR-transgenic mice, whereas no bone marrow toxicity was observed in normal control mice. Administration of excess MRK16 prior to injection of MRK16-PE successfully blocked the effect of MRK16-PE. MOPC-PE, a non-MDR-related control monoclonal antibody conjugate, did not target and kill multidrug-resistant bone marrow cells in MDR-transgenic mice. Thus, these immunological approaches to reversing multidrug resistance appear to be both specific and effective.

Alkaloids↗
PubMed1990

Structural characteristics of compounds that modulate P-glycoprotein-associated multidrug resistance.

Multidrug resistance is mediated by a membrane-bound protein, P-gp, that functions as an energy dependent efflux system to reduce the intracellular concentration of anticancer drugs by binding to these drugs and actively exporting them from the cell. Compounds that interact with P-gp and compete with anticancer drug binding modulate the degree of drug resistance and therefore enhance the cytotoxicity of anticancer drugs against the resistant cell. Effective modulators share certain physical and chemical properties including octanol/water partitioning and molecular size, but the physical properties of size and shape seem to correlate best with modulator effectiveness. Using a photoactivatable analog of vinblastine as a probe, together with a semi-synthetic series of structurally homologous reserpine and yohimbine analogs, the need for two planar aromatic domains and a basic nitrogen atom was established within the structural context of these compounds. The use of three-dimensional comparisons was extended to examine important structural features in other modulator types such as the condensed-ring aromatics. This approach indicates that structural similarities between different classes of compounds are present in compounds recognized by the MDR phenotype. These studies emphasize the importance of a ligand-receptor relationship for modulators of MDR, and begin to define the P-gp-binding pharmacophore. It is likely that this approach will be useful in directing the de novo synthesis of compounds that modulate MDR and help to further define the requirements for molecular recognition by this system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Role of oxygen free radical formation in the mechanism of menogaril resistance in multidrug resistant tumor cells.

The mechanisms of action and resistance to menogaril, a clinically active anthracycline antitumor drug, were evaluated in sensitive and doxorubicin-selected multidrug resistant human breast tumor (MCF-7) cell lines. While MCF-7/ADRR cells were highly resistant (250-500-fold) to doxorubicin, they displayed only marginal resistance (10-fold) to menogaril. In contrast to doxorubicin, the mechanism of resistance to menogaril in these cells does not involve differential inhibition of DNA synthesis as measured by thymidine incorporation. P-170-glycoprotein-dependent drug transport did not contribute to resistance as there was no difference in the accumulation and retention of menogaril by sensitive and resistant cell lines. However, there was a 2-fold decrease in oxygen free radical formation in the resistant cells, compared to sensitive cells, in the presence of menogaril. Since resistant cells contain 12-fold higher glutathione peroxidase activity than the parental sensitive cells, the detoxification of hydrogen peroxide may be responsible for the decreased free radical formation and thus, may play a role in the resistance to menogaril.

Antineoplastic Agents↗
PubMed1993

In vivo acquired drug resistance and multidrug resistance gene (MDR1) expression in the KB carcinoma cell line xenotransplanted in nude mice.

We studied the correlation between in vivo responsiveness of KB xenografts to anticancer drugs and the expression level of the human multidrug resistance gene (MDR1) encoding P-Glycoprotein (P-Gp). We established KB xenografts (xeKB3-1 and xeKB8-5) by inoculating these in vitro lines into nude mice. The responsiveness was evaluated by an in vivo chemosensitivity assay (T/C; sensitive, < 50%). Xenograft xeKB3-1 was sensitive to vincristine (VCR) (T/C, 48%), and xeKB8-5 was resistant to VCR (T/C, 72%). We selected a VCR-resistant variant (xeKB3-1-R, T/C, 76%) by treating xeKB3-1 with VCR (1.2 mg/kg, x3) in vivo. The MDR1 expression was evaluated by a semi-quantitative assay using reverse transcription-polymerase chain reaction. A MDR1 expression pattern in xeKB3-1 and xeKB8-5 in vivo was the same as that to KB3-1 and KB8-5 in vitro. The xenograft xeKB3-1-R expressed definitive but significantly lower levels of MDR1 than xeKB8-5. These results suggest that acquired drug resistance is related to minimally enhanced expression of the P-Gp protein/MDR1 gene in KB xenografts in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Quantitative determination of factors contributing to doxorubicin resistance in multidrug-resistant cells.

There is a large discrepancy between the changes in drug accumulation and the changes in drug cytotoxicity that accompany development of anthracycline resistance in multidrug-resistant cells. In our study, a quantitative relationship has been established between reversal of multidrug resistance by resistance modifiers and a concomitant decrease in intracellular levels of doxorubicin measured at equitoxic concentrations (IC50) in CHRC5 and 2780AD multidrug-resistant cells. (IC50 = concentration required for 50% growth inhibition.) We have demonstrated that resistance modifiers like verapamil and Ro 11-2933/001 act by increasing the effectiveness of intracellular doxorubicin, apparently by inducing redistribution of the drug from the cytoplasm to the nucleus of a multidrug-resistant cell, as shown by quantitative fluorescence microscopy. At complete reversal of resistance, as measured directly or inferred by extrapolation, the amount of intracellular doxorubicin at the IC50 as well as the ratio of nuclear doxorubicin to cytoplasmic doxorubicin were the same as those in sensitive cells. These results offer an explanation for the frequently observed discrepancies between drug accumulation and cytotoxicity and also show quantitatively that a decrease in drug accumulation and a change in intracellular drug distribution together are the only determinants of doxorubicin resistance in the multidrug-resistant cells studied.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Potentiation of etoposide and vincristine by two synthetic 1,4-dihydropyridine derivatives in multidrug-resistant and atypical multidrug-resistant human cancer cells.

Newly synthesized 1,4-dihydropyridine derivatives had been screened to determine whether they could overcome vincristine (VCR)-resistance in VCR-resistant (P388/VCR) leukemia-bearing mice, and six compounds had strong reversing ability among the screened compounds. We further determined whether NK-250 and NK-252 among the six compounds could potentiate cytocidal activities of etoposide (VP16) as well as VCR against both multidrug-resistant (MDR) cell line (VJ-300) and atypical MDR cell line (KB/VM-4). Both VJ-300 and KB/VM-4 were derived from the same parental human cancer KB cell line: VJ-300 cells showed enhanced expression of a MDR-specific glycoprotein of molecular weight of 170,000 Da (gp170) while KB/VM-4 cells were selected as teniposide (VM26)-resistant cell line with no expression of gp170. NK-250 and NK-252 potentiated the cytotoxic action of VCR about 2- to 10-fold against KB and KB/VM-4 cells, and they almost completely reversed VCR-resistance in VJ-300 cells. By contrast, NK-250 and NK-252 potentiated the cytotoxic action of VP16 about 2-fold against KB cells while they reversed 5- to 10-fold VP16-resistance in both VJ-300 and KB/VM-4 cells. The reversal effect by NK-250 and NK-252 of VCR-resistance in VJ-300 cells appeared to be due to enhanced cellular accumulation of radioactive VCR through interaction to 170-kDa P-glycoprotein. The potentiation effects by these dihydropyridines of VCR and VP16 on KB or KB/VM-4 cells also appeared to be due to enhanced accumulation of radioactive VP16 or VCR, but the effects might be mediated through other mechanisms, plausibly enhanced cellular uptake of the drugs.

Antineoplastic Agents↗
PubMed2026

Insights into the fate and dynamics of antibiotic resistance in multidrug-resistant Bacillus cereus during in vitro simulated gastrointestinal digestion.

Bacillus cereus, an important pathogen responsible for causing foodborne diseases worldwide, releases pore-forming enterotoxins, which target host epithelial cells, leading to osmotic lysis and ultimately manifesting as diarrheal syndrome. Moreover, some B. cereus strains carry antimicrobial resistance genes that confer multidrug resistance against a spectrum of antibiotics. Characterizing the survival traits of multidrug-resistant (MDR) B. cereus strains in the intestinal microenvironment is essential for developing targeted strategies to effectively manage diarrheal foodborne diseases caused by this pathogen. This study used whole-genome sequencing (WGS) to evaluate the pre- and post-digestion toxigenic potential, antimicrobial resistance profiles, and genetic diversity of MDR B. cereus strains isolated from food samples in Guangdong Province, China. The four B. cereus isolates investigated in this study exhibited a genetic diversity, as determined by multilocus sequence typing analysis of WGS data. All four isolates produced the diarrheal toxins Hbl, Nhe, and CytK to varying levels, indicative of their potential to cause outbreaks of foodborne diseases. Each of the four isolates exhibited resistance to more than three classes of antibiotics, fulfilling the criterion for multidrug resistance. At an initial concentration of 9 log colony-forming units (CFU)/mL, the intestinal concentration of these four isolates crossed the threshold required to induce widespread diarrhea in the general population. Under rice slurry protection, all tested isolates maintained intestinal concentration beyond the threshold when the initial concentration was increased to &#x2265;8 log CFU/mL. Moreover, the upregulations of genes associated with acid tolerance, bile tolerance and stress response were observed in the surviving MDR B. cereus isolates. Digestion markedly altered the antibiotic resistance profiles of the MDR B. cereus isolates. In the absence of a food matrix, the MDR isolates lost their resistance to imipenem, meropenem, amoxicillin-clavulanic acid, and trimethoprim-sulfamethoxazole post-digestion and was influenced by the initial concentration of the strains. In the presence of food matrix rice slurry, the effects of digestion on the antibiotic resistance of MDR B. cereus isolates can be mitigated, enabling them to maintain their antibiotic resistance to the greatest extent. Most remarkably, after digestion, the isolates Bce055 and Bce166 exhibited newly emergent resistance to cefotetan and trimethoprim-sulfamethoxazole, respectively. Our findings clarify the fate of MDR B. cereus isolates in the gastrointestinal tract and inform the development of prevention and control strategies for foodborne diseases caused by this pathogen.

Drug Resistance, Multiple, Bacterial↗
PubMed1988

Radiation resistance in a multidrug resistant human T-cell leukemia line.

In clinical practice, cancers refractory to chemotherapy commonly appear to be comparatively radioresistant. One mechanism by which cancer cells become resistant to chemotherapy is pleiotropic multidrug resistance, characterized by cross resistance to a number of otherwise unrelated heterocyclic antineoplastic agents, including vinca alkaloids, anthracyclines, dactinomycin, and others. We have studied a drug sensitive human leukemia cell line, CEM; a pleiotropic multidrug resistant subline of CEM, CEM/VLB100; VLB-1, a drug sensitive revertant subline arising during in vivo passage of CEM/VLB100; and a methotrexate resistant subline of CEM, CEM-MTX. Using soft-agar colony formation after graded doses of X rays as an endpoint, we found that CEM, CEM-MTX, and CEM/VLB100 had similar terminal slopes (D0 = 0.66 Gy). However, the CEM/VLB100 survival curve had a broader initial shoulder (n = 3.0, Dq = 0.75 Gy) than did CEM (n = 1.6, Dq = 0.25 Gy) or CEM/MTX (n = 1.0, Dq = 0 Gy), suggesting that CEM/VLB100 has an increased capacity to repair radiation-induced DNA damage. This was tested by comparing the cell lines' abilities to accumulate sublethal damage. In split dose recovery experiments, CEM/VLB100 demonstrated increased ability to repair sublethal radiation damage following fractionated irradiation compared with the CEM parental line. Although it no longer demonstrated multidrug resistance, VLB-1 still displayed diminished radiation sensitivity. On the basis of these and other investigators' results, we suggest that diminished radiation sensitivity is separate from, but can be closely associated with, the multidrug-resistant phenotype.

Antineoplastic Agents↗
PubMed1988

Resistance of multidrug-resistant lines to natural killer-like cell-mediated cytotoxicity.

Multidrug resistance (MDR) refers to a complex phenotype that describes a number of features characterized primarily by resistance to a wide range of structurally unrelated drugs. In this paper we investigated the relationship between drug resistance and resistance to NK-mediated cytotoxicity. Studies with two independently selected multidrug-resistant cell lines indicated that increased drug resistance was associated with both an increased resistance to NK-mediated cytotoxicity and increased levels of membrane P-glycoprotein expression. This resistance to cytotoxicity appears to result partly from an alteration in the membrane structure of the target cells inasmuch as there was a reduction in effector:target cell recognition. Resistance to NK-mediated cytotoxicity should be included with the numerous pleiotropic changes associated with the multidrug resistance phenotype.

Cell Line↗
PubMed1988

An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene.

Multidrug resistance in human cells results from increased expression of the mdr1 (P-glycoprotein) gene. Although the same gene is activated in cells selected with different drugs, multidrug-resistant cell lines can be preferentially resistant to their selecting agent. The mdr1 cDNA sequence from vinblastine-selected KB cells, which are uniformly resistant to different lipophilic drugs, was compared with the corresponding sequence from colchicine-selected KB cells preferentially resistant to colchicine. These sequences differ at three positions, resulting in a single amino acid change in P-glycoprotein. These differences result from mutations that occurred during colchicine selection. The appearance of these mutations coincides with the emergence of preferential resistance to colchicine. We have constructed biologically active mdr1 cDNA clones that express either wild-type or mutant P-glycoprotein. Multi-drug-resistant transfectants obtained with the mutant sequence were characterized by increased relative resistance to colchicine compared with transfectants obtained with wild-type sequence. mdr1 mutations are therefore responsible for preferential resistance to colchicine in multidrug-resistant KB cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Multidrug resistance in heart transplant patients: a preliminary communication on a possible mechanism of therapy-resistant rejection.

Multidrug resistance refers to a complex cellular phenotype, the hallmark of which is cross-resistance to multiple drugs, for example, chemotherapeutic agents, that are unrelated to the selecting agent in structure, cellular target, and mode of action. The expression of this multidrug resistance is connected with the overexpression of P-glycoprotein. By applying the method of immunocytochemical assay, we have demonstrated the appearance of the multidrug-resistant phenotype (P-glycoprotein+ cells, multidrug-resistant cells) in mononuclear cells of the peripheral blood from 32/49 patients receiving triple-drug (azathioprine, steroids, cyclosporine) immunosuppressive therapy after heart transplantation. In the group of patients showing not only the presence of cells with multidrug-resistant phenotype in the peripheral blood, but also a significant increase in the number of these cells during the interval of observation (0 to 767 days)-16/32/49 cases--a significantly increased incidence of acute rejection episodes could be demonstrated. This supports the hypothesis of a possible existence of a therapy-resistant form of acute rejection, with an involvement of mechanisms of multidrug-resistance playing a role in its causal development.

ATP Binding Cassette Transporter, Subfamily B, Mem↗