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)

The clinical utility of anthracyclines like doxorubicin (DOX) and daunorubicin (DNR) for treatment of multiple myeloma (MM) is limited by the occurrence of multidrug resistance (MDR). Highly lipophilic anthracyclines like idarubicin (IDA) might circumvent MDR and thereby enhance chemotherapeutic efficacy. To determine the efficacy of IDA in myeloma cells, the pharmacokinetics and cytotoxicity of IDA and its major metabolite idarubicinol (IDAol) were compared with those of DNR, DOX, and doxorubicinol (DOXol) in the cell line RPMI 8226-S and two MDR sublines (8226-R7 and 8226-Dox40) that overexpress the drug transporter P-glycoprotein (Pgp). Cytotoxicity assays using MTT (viability) or annexin V (apoptosis) showed a 10-50-fold higher potency of IDA compared with DNR or DOX in the MDR variant cell lines. The difference in cytotoxicity was lower in the sensitive parental cell line (3-fold). These results are explained by a better intracellular uptake of IDA compared to DNR in resistant 8226 cell lines. The Pgp-inhibitor verapamil affected IDA uptake only in the most resistant cell line 8226-Dox40. This indicates that IDA is less sensitive than DNR to transport-mediated MDR. IDAol was at least 32-fold more cytotoxic than DOXol, and more susceptible to Pgp transport than IDA. These studies demonstrate that the efficacy of IDA in MDR MM cell lines is superior to that of DOX or DNR, and that IDA may become an important drug in the treatment of MM, especially in refractory disease.
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PMID:Idarubicin overcomes P-glycoprotein-related multidrug resistance: comparison with doxorubicin and daunorubicin in human multiple myeloma cell lines. 1037 47

Resistance mechanisms to chemotherapy in multiple myeloma include (1) reduced drug concentrations at the target site of action, (2) alterations in the drug target, and (3) inhibition or prevention of drug-induced apoptosis. Recent advances in understanding resistance mechanisms have resulted in the investigation of novel therapies for the treatment of patients with multiple myeloma. P-glycoprotein is a drug transport protein that decreases intracellular drug concentrations at the target site. Valspodar, a third-generation cyclosporine analog, is an inhibitor of P-glycoprotein that currently is being evaluated to potentially overcome this mechanism of drug resistance. P-glycoprotein inhibitors (also known as chemosensitizers) are being investigated for use in combination with chemotherapeutic agents to enhance the apoptotic effect and prevent resistance at the target site. Other novel approaches involve blocking pathways that result in the expression of antiapoptosis factors. Interleukin-6 is an important growth factor in myeloma and has been implicated in drug resistance via an antiapoptosis effect. In vitro blocking of an interleukin-6-dependent pathway with either a JAK inhibitor (tyrphostin, AG490) or STAT3 dominant negative (STAT3-DN) reduced expression of Bcl-xL (an antiapoptosis protein), increased spontaneous apoptosis, and enhanced sensitivity to Fas-mediated apoptosis. In conclusion, several cellular mechanisms reduce the response to drug therapy in multiple myeloma. Future treatment approaches for this condition most likely will involve combinations of agents to enhance response or prevent resistance.
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PMID:Drug resistance in multiple myeloma: approaches to circumvention. 1052 91

The development of refractory disease in acute myeloid or lymphoblastic leukaemias (AML, ALL) and multiple myeloma (MM) is frequently associated with the expression of one or several multidrug resistance (MDR) genes. MDR1, MRP1 and LRP have been identified as important adverse prognostic factors in AML, T-ALL and MM. Recently, it has become possible to reverse clinical multidrug resistance by blocking P-glycoprotein-mediated drug efflux. The potential relevance of these reversal agents of MDR and potential new approaches to treat refractory disease are discussed.
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PMID:Multidrug resistance in haematological malignancies. 1080 91

Pleiotropic resistance to treatment remains one of the major reasons for therapeutic failures in patients with multiple myeloma. Myeloma cells are frequently resistant to physiological inducers of cell death prior to chemotherapy. Moreover, in the course of treatment cells acquire a multidrug resistant (MDR) phenotype, making eradication of the tumor even more difficult. A necessary prerequisite for circumventing complex pleiotropic resistance is therefore defining the signaling pathways that execute death in myeloma cells. This review discusses evidence that cytokine-expressing autologous tumor cell vaccine may be an efficient tool for elimination of both intrinsically resistant myeloma cells as well as cells with acquired MDR in murine models. The vaccine was similarly potent against wild type cells that were resistant to several death receptor ligands, and their isogenic sublines selected for P-glycoprotein-mediated MDR. The anti-myeloma effect of the vaccine was mediated by granzyme B/perforin-secreting cytotoxic T-lymphocytes. This is an example of therapeutic strategy directed at utilizing death pathways that are preserved in pleiotropically resistant tumor cells.
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PMID:Alternative pathways of cell death to circumvent pleiotropic resistance in myeloma cells: role of cytotoxic T-lymphocytes. 1081 48

Although melphalan has been used as a therapeutic reagent for multiple myeloma, many patients become refractory. To elucidate the mechanism of resistance to melphalan, we generated a melphalan-resistant myeloma cell line, KHM-11(EMS), by treating a parental line, KHM-11, with a mutagen, ethylmethanesulfonate. KHM-11(EMS) is 55 times more resistant to melphalan. gamma-Glutamylcysteine synthetase, P-glycoprotein, multidrug-resistance-associated protein, lung-resistance-related protein and the Bcl-2 family of proteins were not responsible for the drug resistance in KHM-11(EMS). Intracellular incorporation of melphalan to myeloma cells was determined by using [(14)C]-labeled melphalan. Accumulation of melphalan in KHM-11(EMS) was 43% of KHM-11, while the efflux rates were comparable in both cell lines. The uptake of melphalan was inhibited by the addition of L-phenylalanine, indicating that melphalan is incorporated through the L-phenylalanine transporter as reported previously. Expression of CD98, which was recently cloned as an L-phenylalanine transporter, was 6-fold decreased in KHM-11(EMS), suggesting that CD98 may be correlated with the incorporation of melphalan. CD98 expression and incorporation of melphalan were analyzed in fresh purified myeloma cells from 5 patients. All myeloma cells from 4 cases expressed CD98 at a high level and incorporated melphalan. However, tumor cells from 1 case expressed CD98 at low levels and did not incorporate melphalan. Taken together, reduced melphalan uptake could be responsible for the drug resistance in KHM-11(EMS), and down-regulation of CD98 may be related to this phenomenon. Further investigation of the correlation between impaired drug uptake and down-regulation of CD98 in myeloma cells should be important to understand the mechanism of resistance to melphalan.
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PMID:Down-regulation of CD98 in melphalan-resistant myeloma cells with reduced drug uptake. 1094 Jun 52

We established a rapid and sensitive ex vivo bioassay to detect the multidrug resistance (MDR)-inhibitory activity of SDZ PSC 833 ([3'-keto-Bmt1]-[Val2]-cyclosporin (PSC 833)) in two RPMI 8226 human myeloma sublines (parent 8226 and doxorubicin-resistant subline Dox6) in 75% human serum. In vitro sensitivity of the tumor to doxorubicin was determined by 3-h drug exposure growth inhibition assay (MTT assay). PSC 833 in serum restored the IC50 of doxorubicin in the P-glycoprotein (P-gp)-positive resistant subline to the same level as in the sensitive cells at 1 microg/ml, which has been shown to be an achievable concentration in clinical trials. In addition, the cytotoxic effect of doxorubicin was enhanced by PSC 833 in the sera of the patient in whom the blood level was 705.7 ng/ml. However, 10 microg/ml PSC 833 in serum does not cause a complete recovery in the IC90 of doxorubicin in the resistant sublines. This MDR-inhibitory activity was supported by the finding that PSC 833 in serum does not increase accumulation of rhodamine 123 in doxorubicin-resistant cells in an in vitro functional assay. The present study provides evidence that PSC 833 in human serum is effective to modulate P-gp-mediated MDR but insufficient for the reversal of MDR from the clinicopharmacological point of view.
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PMID:A bioassay for the activity of PSC 833 in human serum for modulation of P-glycoprotein-mediated multidrug resistance. 1103 63

Multiple myeloma remains an incurable cancer. In recent years, progress in different drug classes has improved outcomes, but management has become more complicated. Areas such as prognostic classification, the increased use of high-dose chemotherapy with autologous stem-cell rescue, and a wider array of ancillary drugs must be integrated into recommendations for a consolidated treatment plan. Estimating prognosis is dependent on both clinical features and a growing list of laboratory tests. Autologous transplantation has been applied to an increasing proportion of patients, at different points in the disease process. Besides the age cut-off issue, there are still significant treatment choices to be made within the transplant technique. Newer drugs, most recently, thalidomide (Thalomid), may offer benefits independent of conventional cytotoxic drugs or steroids. Use of ancillary drugs, such as bisphosphonates, interferon, P-glycoprotein blockers, antibiotics, and growth factors, are also discussed. For the future, immunotherapy in the posttransplant setting appears promising. Ultimately, basic research must identify intracellular targets for the development of specific new-generation drugs.
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PMID:Considerations in the management of myeloma. 1119 22

Valspodar (PSC-833) is a derivative of cyclosporin but devoid of the immunosuppressive and nephrotoxic properties seen in cyclosporin A. It exhibited high affinity binding to Mdr1 P-glycoprotein (P-gp) and demonstrated multidrug resistance-reversing activity superior to cyclosporin A and verapamil both in vitro and in vivo. Preclinical and phase I/II clinical data have indicated that plasma levels of PSC-833 with multidrug resistance-reversing activities are achievable. Potent inhibition of intestinal, hepatobiliary and blood-brain barrier P-gp function has been demonstrated. Since valspodar is also a substrate of cytochrome P450 3A (CYP3A), dual interactions of this compound with P-gp and CYP3A are the basis for the pharmacokinetic interactions seen in preclinical and clinical studies. A new formulation of the drug has recently been developed with better oral bioavailability (60%) and less interindividual variability. The toxicity profiles of valspodar are acceptable and dose-limited by transient and reversible cerebellar ataxia. It has shown multidrug resistance-modulating activities towards acute myeloid leukemia, multiple myeloma and ovarian cancer in phase I/II clinical trials. Phase III studies with respect to these three diseases are ongoing.
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PMID:Technology evaluation: Valspodar, Novartis AG. 1124 78

The clinical application of resistance reversal drugs for patients with hematologic malignancies is reviewed. The phenomenon of multidrug resistance versus other mechanisms are discussed. The pump-like mechanisms of P-glycoprotein, multidrug resistance associated protein, lung resistance protein and of other ATP binding cassette transporter proteins are reviewed briefly, as well as the important substrate drugs and pump-blocking compounds. The problems associated with resistance protein assays in clinical samples and the concept of prognostic versus therapeutic clinical relevance are described, within the context of selected hematologic malignancies. Toxicities and treatment outcomes of phase II and III trials of reversal agents in lymphoma, multiple myeloma, myelodysplastic syndromes, acute myeloid leukemia and blast phase of chronic myeloid leukemia are reviewed. Finally, current options for on-study management of relapsed or refractory hematologic malignancy patients are discussed.
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PMID:Application of Resistance Reversal Agents in Hematologic Malignancies; Malignancy; Current Clinical Practice. 1139 34

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


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