Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in intracellular drug localization accompany doxorubicin resistance in multidrug resistant tumor cells. The purpose of this study was to develop a method to quantify these changes and so detect different levels of resistance. Tumor cells were incubated with the fluorescent anthracycline doxorubicin (excitation at 480 nm; emission maximum at 560-590 nm) and were quantified using laser scanning microscopy. The fluorescent mode was used to record the intracellular drug distribution, whereas the absorption mode was used to define the nuclear and cytoplasmic boundaries. The cell compartments were delineated interactively on an image processing system and the ratio nuclear fluorescence/cytoplasmic fluorescence (N/C ratio) was determined. N/C ratios were: 1.8 in the Chinese hamster ovarian cell line AUXB1 and 0.1 in its MDR subline CHRC5; 3.8 in the human squamous lung cancer cell line SW-1573 and 1.8 and 0.4 in its MDR sublines SW-1573/2R120 and SW-1573/2R160, respectively; and 3.6 in the human myeloma cell line 8226/S and 2.1 and 1.0 in its MDR sublines 8226/Dox4 and 8226/Dox40, respectively. The doxorubicin distribution was independent of the doxorubicin concentration within a range from 1-32 microM. Furthermore, the progressive mean of the nuclear/cytoplasmic doxorubicin fluorescence ratio showed that a minimal sample size of 30 cells is necessary for reliable results. The results of two independent assessments showed a high reproducibility (r = 0.97). Thus, with the method described in this paper, it is possible to detect relatively low levels of doxorubicin resistance (factor 8).
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PMID:Quantification by laser scan microscopy of intracellular doxorubicin distribution. 145 89

We report a case of ectopic salivary amylase-producing IgA- lambda-type multiple myeloma. A 70-year-old man was admitted because of anemia and renal failure. After chemotherapy for eight months, the serum amylase markedly increased. Amylase activity in the supernatant of cultured myeloma cells, which were obtained from the bone marrow, also increased. The myeloma cells expressed MDR-1/P-glycoprotein). The case implies the association of drug resistance and the ectopic amylase production in a case of multiple myeloma.
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PMID:[Ectopic salivary amylase-producing IgA- lambda-type multiple myeloma with expression of MDR-1/P-glycoprotein]. 171 26

We examined the effectiveness of a previously characterized plasma cell-reactive monoclonal antibody (MoAb), MM4, in eliminating multi-drug resistant (MDR1) multiple myeloma (MM) clonogenic colony-forming cells (CCCs). MDR1 sublines with 6-fold (RPMI8226/DOX6) and 40-fold (RPMI 8226/DOX40) resistance to doxorubicin (DOX) were selected from the chemosensitive MM parent line RPMI 8226/S. Both sublines remained reactive with plasma cell MoAbs MM4 and PCA-1, as measured by flow cytometric immunophenotype analysis. MM4 and rabbit complement (C') were cytotoxic to MDR DOX6 (74 +/- 8.5%) and DOX40 (75 +/- 11.3%) cells as well as to chemosensitive 8226/S (80 +/- 5.6%) cells. Treatment with MM4 + C' depleted up to 3 logs of chemosensitive and MDR myeloma CCCs (8226/S: 99.26 +/- 0.52%; DOX6 99.91 +/- 0.08%' DOX40 99.15 +/- 0.55%). In addition, this approach abrogated the selfrenewing capacity of chemoresistant and MDR1 myeloma cell lines, according to doubling time analyses. By comparison, the P-glycoprotein-reactive MoAb MRK-16 and C' was effective in deleting MDR1 CCCs (DOX10: 95.71 +/- 2.51%; DOX40: 99.61 +/- 0.43%) but affected chemosensitive myeloma CCCs only slightly (5.93 +/- 14.52%). When DOX40 cells were mixed with normal bone marrow (BM) in a ratio of 10:90 (MM:BM), treatment with MM4 plus C' deleted MM CCCs (98.80 +/- 0.71%) without affecting the majority of normal BM progenitors. The combination of MM4 and MRK-16 did not enhance MDR myeloma CCC depletion. These observations suggest that MM4 + C' may be useful for depleting MDR as well as chemosensitive myeloma clonogenic cells from human bone marrow.
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PMID:Elimination of chemoresistant myeloma clonogenic cells from human bone marrow by monoclonal antibody and complement. 230 79

The huge discrepancies in the proportion of tumors positive for P-gp observed in the literature limit any definite conclusions, except for the urgent need for standardized methods to compare results. It is well known by scientists that only positive results are published. For this reason, the frequency of P-gp expression in leukemia and lymphoma may be overestimated. The role of the MDR phenotype in clinical resistance is also not clearly demonstrated, because of the frequent association of other markers of bad prognosis on the same subset of cells (CD34, CD7 in leukemia). Hematologic malignancies are the most extensively studied tumors for drug resistance, and they could be a model for the therapeutic use of modifier agents. Many clinical trials are now ongoing in myeloma, acute leukemia, and lymphoma, with new modifier agents. The standardization of methods for P-gp, permitting large multicentric studies, and the results of randomized studies with modifier agents will help us know if mdr1 gene overexpression is of clinical importance in hematologic malignancies.
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PMID:P-glycoprotein in adult hematologic malignancies. 764 63

Monoclonal gammopathy of undetermined significance (MGUS) is different from multiple myeloma (MM) by a low proliferation and by its indolent clinical course. In this study, two biological parameters were investigated which mark the transition from MGUS to MM, i.e. expression of the P-170 glycoprotein associated with the multidrug resistance phenotype (MDR-1) and expression of the natural killer cell antigen. CD56. Strong MDR-1 expression was found in plasma cells of 32/38 untreated MGUS as compared with 33/105 untreated MM stage I-III (84% v 32%, P < 0.001) and in 0/10 normal plasma cell samples. CD56 expression in high density was present in 43/57 analysed untreated MM but in none of 23 MGUS (78% v 0%, P < 0.0001). Plasma cells did characteristically show a low Ki-67 proliferation index in 14/15 MGUS patients (mean 0.05%, range 0-0.2%) and a higher index in 25 analysed MM patients (mean 2.31%, range 1-7%, P < 0.03). These data indicate that MDR-1 expression together with absence of CD56 expression and a low proliferation index can be used to separate MGUS from MM.
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PMID:Analysis of multidrug-resistance (MDR-1) glycoprotein and CD56 expression to separate monoclonal gammopathy from multiple myeloma. 767 88

Resistance to chemotherapeutic agents in neoplastic cells is often mediated by expression of P-glycoprotein, which functions as a drug-efflux pump for a broad range of substrates. We have used a combination of patch clamp and video-imaging techniques to examine the expression and drug-efflux function of P-glycoprotein and to determine the possible correlation with swelling-activated chloride channels in drug-sensitive and -resistant cell lines. Two pairs of cell lines were used in these experiments: (a) control NIH-3T3 cells and a corresponding MDR1-transfectant; and (b) control 8226 myeloma cells and a derivative cell line selected for resistance to chemotherapeutic agents. Control cells lacked detectable P-glycoprotein expression based on Western blotting, immunofluorescence staining with a specific monoclonal antibody, and a functional assay of rhodamine-123 (R123) efflux. Resistant cells expressed P-glycoprotein at high levels and rapidly exported R123. During whole-cell recording using either hyperosmotic pipette solution or hypoosmotic Ringer solution, cell swelling was accompanied by Cl- channel opening in all four cell lines. The rates of induction, biophysical properties and magnitudes of Cl conductance (gCl) were indistinguishable between control and corresponding multidrug-resistant cells: gCl reached 0.96 +/- 0.31 (n = 14) and 0.83 +/- 0.31 nS/pF (mean +/- SD; n = 31) in NIH-3T3 and NIH-3T3/MDR cells, respectively; and 0.31 +/- 0.20 (n = 9) and 0.37 +/- 0.22 nS/pF (n = 7) in 8226 and 8226/Dox40 cells, respectively. gCl exhibited moderate outward rectification in symmetrical Cl- solutions, with a rectification ratio of 1.4 at +/- 50 mV. Cl- channels slowly closed during strong depolarization beyond +60 mV. Using video-imaging techniques with SPQ as a fluorescent probe, we monitored Cl(-)-channel opening in intact drug-sensitive and -resistant cells. gCl, measured either with whole-cell recording or SPQ imaging, was blocked by DIDS (voltage-dependent Kd < 50 microM at +40 mV), NPPB (Kd approximately 30 microM), and tamoxifen (complete and irreversible block approximately 10 microM). None of these blockers inhibited R123 efflux. NPPB accelerated R123 efflux, an effect that was mimicked by CCP, a mitochondrial uncoupler. In contrast, verapamil selectively blocked R123 efflux (Kd = 0.3 to 0.5 microM); 10 microM left gCl unaltered. Induction of gCl was not affected by vincristine or doxorubicin in the pipette solution. Moreover, the rate of R123 efflux did not change during cell swelling. We conclude that P-glycoprotein and swelling-activated chloride channels function independently and are separable by expression and by pharmacological sensitivities.
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PMID:Swelling-activated chloride channels in multidrug-sensitive and -resistant cells. 769 67

We have used single-cell photometry to measure intracellular pH (pHi) for several MDR cell lines constructed by stably transfecting LR73 chinese hamster ovary fibroblasts with mutant and wild type murine MDR 1 genes. In addition, plasma membrane electrical potential (delta psi) has been measured for the same cells by the K+/valinomycin null point titration method using the ratiometric styryl probe di-4-ANEPPS. Both the untransfected, parental cell line and a cell line expressing substantial mutant MDR 1 protein (K432R/K1074R) that is unable to confer the MDR phenotype are found to have delta psi > or = -40 (+/- 5) mV and pHi < or = 7.16 (+/- 0.03) units. In contrast, MDR cell lines constructed by transfecting wild type mu MDR 1 cDNA are found to exhibit delta psi from 15 to 19 mV lower and pHi from 0.13 to 0.34 units higher. A cell line that overexpresses crippled MDR protein (S941F) that is not resistant to colchicine or doxorubicin, but which is resistant to vinblastine [Gros, P., Dhir, R., Croop, J., & Talbot, F. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 7289-7293], exhibits elevated pHi and slightly elevated delta psi, relative to LR73. Northern and western blot analyses confirm the substantial overexpression of the mu MDR genes and proteins in these lines, as well as the mild overexpression of endogenous hamster p-GP mRNA in some lines. In general agreement with previous studies that examined myeloma cells overexpressing hu MDR 1 protein [Roepe, P.D., Wei, L.-Y., Cruz, J., & Carlson, D. (1993) Biochemistry 32, 11042-11056] we find that overexpression of wild type mu MDR 1 protein inhibits Cl(-)- and -HCO3-dependent pHi homeostasis. Via single-cell photometry studies we now conclude that this is due to inhibition of Na(+)-independent Cl-/-HCO3 exchange (strict anion exchange or AE). As concluded previously for other MDR cells, decreased AE activity is not due to decreased expression of the exchanger; in fact, again similar to previous work [Roepe et al. (1993) Biochemistry 32, 11042-11056], we find increased levels of AE mRNA in some MDR cell lines. Models that may explain these data that are also consistent with the known physiology of cells that endogenously express MDR protein are suggested. These data are consistent with a model for MDR protein function wherein overexpression of the protein decreases delta psi and/or elevates pHi via Cl(-)- and -HCO3-dependent mechanisms.
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PMID:Transfection of mu MDR 1 inhibits Na(+)-independent Cl-/-HCO3 exchange in Chinese hamster ovary cells. 791 82

Median survival in patients with multiple myeloma, which amounted to 6-12 months during the pre-chemotherapy era, was improved to 28-43 months following the introduction of chemotherapy. Usually patients with stage II or III myeloma require treatment. Conventional chemotherapy with melphalan-prednisone is undertaken if their prognosis is good; in case of poor prognosis and good general condition, a more aggressive polychemotherapy is given. High-dose melphalan therapy alone induces high remission rates, but fails to prolong remission duration or survival. Resistance to cytostatic drugs due to the p-glycoprotein coded by the MDR-gene is treated by a combination of cyclosporin-A or verapamil and VAD. For the treatment of relapses or of primarily resistant patients several second-line regimens are available. As remission maintenance therapy, interferon has so far yielded the best results. Trials of other cytokines such as interleukin-2 and interleukin-4 are still inconclusive. For autologous bone marrow transplantation, primary reduction of the tumour mass by conventional polychemotherapy is recommended. Subsequently, high-dose melphalan or cyclophosphamide-busulfan--with or without total body irradiation--is used for conditioning and followed by the transplantation of either autologous bone marrow or peripheral blood stem cells. Significantly higher remission rates and longer survival of the patients may be expected. Allogenous bone marrow transplantation is burdened with a high early mortality rate, but it also promises longer disease-free survival times. Bone marrow transplantation should be performed as early as possible in the course of the disease. More controlled studies are required before a definite evaluation of its efficacy is possible.
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PMID:[The treatment of multiple myeloma]. 794 91

In order to clarify the mechanism of drug resistance in human myeloma cells, we investigated the expressions of DNA topoisomerase I and topoisomerase II gene and the genes possibly related to drug resistance; multi-drug resistant gene 1 (MDR-1), glutathione S-transferase class pi gene (GST-pi), by Northern blotting. Myeloma cells in eight of 15 cases prior to chemotherapy expressed topoisomerase I mRNA considerably, while the expression of topoisomerase II mRNA was detected weakly in only one of 16 myeloma patients. There was not any correlation between expression of topoisomerase I mRNA and clinical drug resistance. Significant expression of MDR-1 mRNA and P-glycoprotein was not detected in 25 cases of multiple myeloma prior to chemotherapy and even after several courses of VAD (vincristine, adriamycin and dexamethasone) therapy by Northern blotting and immunostaining using monoclonal anti-P-glycoprotein antibody (MRK-16), respectively. On the other hand, 16 of 21 myeloma cases showed significant expression of GST-pi protein and GST-pi mRNA with the various strengths, but there was no apparent correlation between GST-pi mRNA expression and clinical response. Therefore these data suggest that expression of the genes we tested may not determine the level of drug resistance in multiple myeloma, but lower or no significant expression of topoisomerase II mRNA in most myeloma cells indicates the possibility that topoisomerase II inhibitors such as VP-16 and topoisomerase II-mediated cytotoxic drugs such as adriamycin, are not so effective for the treatment of multiple myeloma.
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PMID:Expressions of DNA topoisomerase I and II gene and the genes possibly related to drug resistance in human myeloma cells. 809 26

Few effective treatments are available for patients with multiple myeloma that is resistant to vincristine-doxorubicin by continuous infusion with high dose dexamethasone (VAD). In order to modulate p-glycoprotein, the multidrug resistance gene product, we administered a VAD-cyclosporine combination to patients with confirmed resistance to VAD. Twenty-five patients with multiple myeloma resistant to VAD received cyclosporine 4 mg/kg infused over 2 hours followed by a continuous infusion of 10 mg/kg/24 hrs for a total of 108 hours. VAD was given concurrently as a continuous infusion of vincristine 0.3 mg and doxorubicin 9 mg/m2 daily for 4 days with oral dexamethasone 20 mg/m2/day for 4 days beginning on days 1, 9 and 17. Clinical response and toxicity were correlated with MDR expression in plasma cells and the effects of cyclosporine on liver function. Six of 25 patients responded (24%; 95% CI 9-45%) with a median remission time of 7 months. Clinical response did not correlate with either the measured or the calculated MDR expression in plasma cells. Responses occurred more frequently in patients who developed high cyclosporine blood levels and paralytic ileus. The occasional benefit from VAD-cyclosporine for resistant multiple myeloma appeared to be due to a higher bioeffective dose of VAD rather than successful modulation of MDR.
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PMID:VAD-cyclosporine therapy for VAD-resistant multiple myeloma. 857 63


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