Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tc-99m 2 methoxy-isobutyl-isonitrile (99mTc-MIBI), also called Sestamibi, is a safe and effective scanning agent in solid tumours. Its use in imaging lesions in multiple myeloma has been studied in 21 patients with either multiple myeloma (19/21) or monoclonal gammopathy of undetermined significance (MGUS) (2/ 21). 99mTc-MIBI scanning was positive in 14 patients, 13 with active myeloma and one patient with MGUS showing possible transformation to a more accelerated phase. In seven patients 99mTc-MIBI scanning was negative. In four of them, the result was unexpected, as they had the features of active myeloma. All four were either primarily or secondarily resistant to chemotherapy, with high total cumulative doses of doxorubicin. Overexpression of P-glycoprotein associated with multidrug resistance could be a factor, as it has been shown that 99mTc-MIBI is actively eliminated from the cell by P-glycoprotein. With this assumption, sensitivity of the scanning technique in this series is 100%, and the specificity 88%. No toxicity was experienced by any patient. 99mTc-MIBI scanning is a useful adjunct to the investigation of multiple myeloma, and may have potential as an in vivo test for multidrug resistance.
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PMID:The use of 99mTc-MIBI scanning in multiple myeloma. 895 99

Although chemotherapy effectively reduces the plasma cell burden in multiple myeloma (MM), the disease recurs. MM includes circulating and bone marrow (BM) localized components. A large majority of circulating CD11b+ MM B cells (81%) express an IgH VDJ rearrangement identical to that of autologous BM plasma cells. Unlike plasma cells, these monoclonal circulating B cells exhibit dye and drug transport activity before and throughout chemotherapy. Drug resistance was measured as the ability to export the fluorescent dye Rhodamine123 (Rh123) or the drug adriamycin, using flow cytometry. The role of P-glycoprotein 170 (P-gp), the multidrug transporter, was defined by cyclosporin A (CsA)-sensitive dye export. Only 8% to 11% of BM-localized plasma cells exported dye with the majority retaining dye, identified as bright staining. Circulating leukemic plasma cells were also unable to export dye and remained Rh123(bright). However, 53% of circulating clonotypic MM B cells exhibited CsA-sensitive dye export. BM plasma cells taken before or after initiation of first line chemotherapy were equally unable to export dye. Thus in myeloma, differentiation to the plasma cell stage is accompanied by a loss of P-gp function, although P-gp phenotypic expression is retained. In contrast, for monoclonal gammopathy of undetermined significance (MGUS), 54% of BM-localized plasma cells exported dye, comparable to the 53% of circulating MGUS B cells that also exported dye, suggesting that the apparent defect in P-gp function is unique to myeloma plasma cells. Virtually all BM plasma cells in MM retained the drug adriamycin, consistent with their initial drug sensitivity in vivo, in contrast to circulating MM B cells, or to T cells in BM or blood. Thus, circulating B cells appear to be the predominant drug resistant component of the MM B-lineage hierarchy. This report suggests that successful therapeutic strategies will be those that target circulating B cells. Chemosensitization methods involving inhibition of P-gp are likely to improve depletion of these cells by compromising their ability to exclude drug. This work suggests that circulating clonotypic B cells should be monitored in clinical trials to confirm their depletion and the overall efficacy of novel treatment strategies.
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PMID:Deficient drug transporter function of bone marrow-localized and leukemic plasma cells in multiple myeloma. 934 62

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