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)

Multiple myeloma is a plasma cell malignancy which is generally incurable in spite of a high initial response to chemotherapy. Relapsing disease commonly heralds an increase in the incidence of drug resistance which is often mediated by the product of the MDR-1 gene, P-glycoprotein (Pgp). One approach to modulating drug resistance due to Pgp overexpression has involved the use of agents known as chemomodulators which inhibit its function. We have developed a human xenograft model of multiple myeloma using the SCID mouse to evaluate the efficacy and toxicities of new MDR-1 chemomodulators. Cyclosporin A (CsA) is a widely used immunosuppressant which has been demonstrated to be a potent inhibitor of Pgp in vitro at concentrations which are clinically achievable. Preliminary studies revealed an acute toxicity in our SCID model which was associated with the combination of CsA and doxorubicin, and which was not observed with either drug alone, nor with cremaphor, the vehicle for CsA. In the current study, non-tumor bearing SCID mice were dosed with doxorubicin or the combination of doxorubicin with cremaphor, verapamil or CsA. Animals were sacrificed and tissues harvested for morphologic examination and for HPLC analysis of doxorubicin levels. In all tissues examined, there was a marked increase in tissue levels of doxorubicin when combined with CsA. Results also revealed a higher incidence and severity of myocardial damage in those animals receiving the combination of doxorubicin and CsA than in those receiving other combinations. The elevations in tissue levels observed with doxorubicin and CsA may contribute to the acute toxicities observed in the SCID mouse model.
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PMID:Cardiotoxicity in the SCID mouse following administration of doxorubicin and cyclosporin A. 884 85

Primary or acquired drug resistance is the major cause of failure of chemotherapy in MM. MDR is associated with expression of a membrane P-gp, which acts as an efflux pump for natural product drugs, such as doxorubicin and vincristine. P-gp expression is observed in extensively treated patients and is a cause of refractoriness to VAD chemotherapy. Among several other non-cytotoxic drugs, cyclosporins modulate the function of P-gp in refractory myeloma cells. Early clinical trials with verapamil and cyclosporin have shown that these can be combined with VAD. In patients treated with drug-resistance modifiers, there is, besides an effect on the tumour cell, also an increased plasma exposure to several cytostatic drugs, which is mediated through inhibition of biliary efflux. Thus, the clinical effect of drug modulation may result from inhibition of tumour P-gp and from altered drug pharmacokinetics. Several trials are now in progress in order to evaluate the clinical benefit of resistance modulators in myeloma.
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PMID:Modulation of multidrug resistance in multiple myeloma. 884 75

Multiple myeloma (MM) is a B cell malignancy characterized by the expansion of monoclonal Ig-secreting plasma cells with low proliferative activity. It is postulated that inhibition of physiologic cell death is an underlying factor in the pathophysiology of MM. The development of chemoresistance is a common feature in patients with MM. In the present studies, hexamethylene bisacetamide (HMBA), a hybrid polar compound that is a potent inducer of terminal differentiation of various transformed cells, is shown to inhibit the growth of several human myeloma cell lines (ARP-1, U266, and RPMI 8226), including doxorubicin-resistant RPMI 8226 variants that overexpress the multidrug-resistance gene, MDR-1, and its product, p-glycoprotein. In addition to growth arrest and suppression of clonogenicity, HMBA induces apoptosis both in freshly isolated human myeloma cells and in cell lines, as determined by morphologic alterations, cell cycle distribution and endonucleosomal DNA fragmentation. Further, HMBA decreases BCL-2 protein expression in myeloma cells within 12-48 hr. Overexpression of BCL-2 protein in ARP-1 cells confers resistance to HMBA-induced apoptosis. Taken together, these data suggest that HMBA is a potent inducer of apoptosis in human myeloma cells, which may act through suppressing the anti-apoptotic function of the bcl-2 gene. HMBA, and related hybrid polar compounds, may prove useful in the management of this presently incurable disease.
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PMID:Hexamethylene bisacetamide induces programmed cell death (apoptosis) and down-regulates BCL-2 expression in human myeloma cells. 941 46

We investigated the effects of MCNU (methyl-6)3-(2-chloroethyl)-3-nitrosoureido)-6-deoxy- alpha-D-glucopyranoside), a nitrosourea anti-tumor agent developed in Japan, on cell growth and differentiation in five human myeloma cell lines and compared it with relative expression levels of MDR-1 gene. Although 10 microg/ml of MCNU inhibited cell growth in KMM-1 and KMS-5 lines, other three cell lines required 20-40 microg/ml of MCNU to obtain similar growth inhibition. Accumulation up to the G2 phase of the cell cycle was observed in KMM-1 and KMS-5 lines and the cloning efficiency of KMS-5 cells was reduced by MCNU. On the other hand, expression of surface markers on these lines was not altered remarkably except for increased expression of CD38 on KMS-5 cells. However, the effect of MCNU on these cell lines did not correlate to relative expression levels of MDR-1 gene analyzed by RT-PCR. MCNU may inhibit the growth of myeloma cells by the accumulation of these cells up to the G2 phase, but may not affect their differentiation.
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PMID:Effect of the nitrosourea anti-tumor chemotherapeutical agent MCNU on five human myeloma cell lines. 962 26

Multiple myeloma is not a curable disease, and most patients relapse after plateau phase. Drug resistance is a major problem in effective chemotherapy in this kind of disease. Current approaches are aimed at reversing or preventing drug resistance late in the disease. We studied a drug resistance marker, P-glycoprotein (P-gp), in a total of 43 patients with monoclonal gammopathy. This group included eight with monoclonal gammopathy of undetermined significance (MGUS), five with plasmacytoma (PCM), nineteen with multiple myeloma (MM; six newly diagnosed, seven plateau, five refractory, one relapse) and eleven amyloidosis (seven newly diagnosed, four after treatment). Using 3-color flow cytometry, a plasma cell gate was selected on the basis of CD38+/45-(dim) staining and the population was examined for the expression of P-gp using two monoclonal antibodies (MRK16 and UIC2). P-gp expression was positive on marrow plasma cells in 42/43 patients. The resistance index (RI) in these cases (range 2.0-7.07) is comparable to that in the positive cell line KG-1A (3.05-3.08). In 2 of 5 patients with refractory MM, the RI for P-gp (5.4, 6.36) was higher than in plateau phase. These data suggest that relative resistance due to the P-gp mechanism is likely to be an intrinsic property of plasma cells in monoclonal gammopathies and may provide a partial explanation as to why these diseases always relapse. The results of our study support strategies for MDR reversal earlier in the course.
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PMID:Is multidrug resistance (P-glycoprotein) an intrinsic characteristic of plasma cells in patients with monoclonal gammopathy of undetermined significance, plasmacytoma, multiple myeloma and amyloidosis? 964 71

Recombinant human hematopoietic growth factors are widely used in the treatment of multiple myeloma (MM) especially due to the increasing role of autologous blood stem cell transplantation (ABSCT). We report a patient with MM in whom rapid extramedullary progression of disease was observed during stem cell mobilization with G-CSF. In 56-year-old man with relapsing IgG lambda MM myeloablative therapy with ABSCT was planned 2 years after diagnosis. G-CSF is increasing doses was used for mobilization. Ten days after the start of G-CSF therapy 2 extramedullary (subcutaneous) myeloma infiltrates appeared. For the second mobilization high dose cyclophosphamide and VP-16 with subsequent G-CSF was used. During the time of chemotherapy tumour infiltrates disappeared, however, after one week of G-CSF treatment rapid progression of disease with the formation of multiple extramedullary infiltrates occurred and the patient died in June 1996. Small pieces of subcutaneous tumour infiltrates were removed at autopsy and immediately frozen in liquid nitrogen. Using the panel of specific antibodies the expression of cytokine receptors (IL-1, 2, 3, 6, 7, 8, 10, SCF, gp130, G-CSF, GM-CSF, EPO) and Fas, Pgp and 24-34 kD multidrug resistance-associated protein were examined. However, no expression of cytokine receptors on tumor cells was found. On the contrary, high positivity of surface MDR associated proteins was observed.
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PMID:[Progression of multiple myeloma during treatment with recombinant G-CSF and absence of G-CSF and IL-6 cell surface receptors on malignant cells]. 992 31

The cytotoxic activity of the non-steroidal anti-inflammatory agent ibuprofen to human promyelocytic leukemia cell line HL-60, its multidrug-resistant subline HL-60/VCR (MDR-1 gene coded P-glycoprotein), as well as myeloma U266 and B-lymphoblastoid ARH-77 cell lines was demonstrated with the aid of flow cytometric analysis. Ibuprofen inhibited proliferation and induced apoptosis (detected as sub-G0 nuclei, fluorescein diacetate staining, Annexin-V binding cells and agarose electrophoretic detection of nucleosomal DNA fragmentation) in promyelocytic cells and, to a lesser extent, in U266 and ARH-77 cells.
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PMID:Non-steroidal anti-inflammatory agent ibuprofen-induced apoptosis, cell necrosis and cell cycle alterations in human leukemic cells in vitro. 1158 91

The use of multidrug-resistant variant of Sp2/0 mouse myeloma cell line SpEBr-5 as a partner for making mouse hybridoma producing monoclonal antibodies is described here. The resulting hybridoma cell line 1F7 was characterized with a high level of monoclonal antibody production and karyotype containing all normal mouse chromosomes. 1F7 cells were separately selected for resistance to ethidium bromide (EBr) and adriamycin (ADR) and different mechanisms of drug resistance were found in these cell variants. The resistance in ADR-selected 1F7 cells was due to amplification and overexpression of mdr genes. In EBr-resistant 1F7 cells, mdr genes were overexpressed without amplification. Substantially decreased level of Topo II activity in both cell lines also suggests the existence of additional mechanisms for MDR phenotype of hybridoma cells. Finally, adriamycin-resistant 1F7 hybridoma cell variant was found to produce higher level of specific immunoglobulins due to the increased level of Iggamma(2b) heavy chain mRNA.
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PMID:Mouse myeloma cell line Sp2/0 multidrug-resistant variant as parental cell line for hybridoma construction. 1467 50

Multidrug resistance is one of the mechanisms how to explain failure of chemotherapy in patients with different hematological malignancies. In this study we aimed to evaluate and compare the drug resistance in B-cell acute lymphoid leukemia (B-ALL) and multiple myeloma (MM) in association with their immunophenotypes and genotypes. Eleven patients with B-ALL and 14 patients with MM were classified according to prognostic factors. Standard MoAb panel for ALL and triple labeled antibodies (CD38/CD56/CD19) and detection of intracellular light chains for MM were used. Flow cytometric calcein assay was performed for measure of P- glycoprotein (MDR-1) and multidrug resistance associated protein (MRP-1) activity. Markers CD19, CD20 and HLA-DR proved to be useful in identifying cells of B-lymphoid lineage. CD34 progenitor cell antigen was present in high proportion of ALL blasts. Both the abnormal plasmacell populations and their monoclonality in MM were confirmed by immunophenotyping, too. The mean MDR activity factor (MAF) values were not different in patients with MM and B- ALL. However, the mean MRP-1 values in MM were significantly lower than MAF-MDR-1 (1.85+/-3.8 versus 5.92+/-7.45, p=0.05), but we have found lower values in refractory conditions as expected from previous studies of acute myeloid leukemia. The immunophenotyping was helpful in detection of abnormal populations showing no correlation with the MDR. However, in this study we could not confirm high MDR activity despite of the failure of chemotherapy. The calcein assay seems to be useful for quantitative and sensitive measurement of the MDR proteins. The low activity of MDR- 1 and MRP-1 in MM need further clarification, indicating the involvement of different transport in the resistance mechanism.
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PMID:Application of flow cytometry immunophenotyping and multidrug resistance assay in B-cell acute lymphoid leukemia and multiple myeloma. 1573 24

Inactivation of poly(ADP-ribose) polymerase-1 (PARP-1) has been shown to potentiate the cytotoxicity of distinct DNA targeting agents including topoisomerase I inhibitors. On the other hand, the PARP-1 deficient cells exhibited resistance to conventional inhibitors of topoisomerase II such as etoposide or doxorubicin (DOX). Recently, we observed the extreme sensitivity of PARP-1 knock-out (KO) cells to C-1305, a new biologically active triazoloacridone compound. C-1305 permanently arrested the cells in G2-phase of the cell-cycle. These observations prompted us to investigate more thoroughly the susceptibility of PARP-1 KO cells to DOX and to examine the effect of DOX on the progression of cell-cycle. We determined the uptake of DOX and P-glycoprotein (P-gp) expression in mouse cells and compared it with that in human myeloma 8226/Dox40 cells overexpressing P-gp. Exposure of mouse cells to DOX revealed a reduced drug uptake in cells lacking PARP-1. However, combined treatment with verapamil, a potent MDR modulator increased the DOX accumulation. Detailed immunoblotting experiments revealed an approximately threefold higher P-gp level in PARP-1 KO cells as compared with normal counterparts. Interestingly, DOX induced in normal fibroblasts very rapidly G2 arrest whereas in PARP-1 KO cells it blocked primarily the transition between S and G2 resulting in the increase of cells remaining in S-phase. This coincided with the lack of the site-specific phosphorylation of CDK2. Simultaneous inhibition of P-gp in cells lacking PARP-1 resulted in an accumulation of cells in G2. Exposure of mouse cells to high DOX dose activated significantly caspase-3/7 in PARP-1 KO cells.
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PMID:Major contribution of the multidrug transporter P-glycoprotein to reduced susceptibility of poly(ADP-ribose) polymerase-1 knock-out cells to doxorubicin action. 1586 98


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