UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mechanism of action study was performed with 14 novel DNA binding agents characterized structurally as 2-(arylmethylamino)-1,3-propanediols (AMAPs). Correlations between 8226 myeloma cell colony formation and DNA damage were performed using soft agar colony-forming assays and alkaline elution filter techniques respectively. The frequency of double-stranded breaks (DSBs), single-stranded breaks (SSBs) and DNA-protein cross-links were compared with cell growth inhibitory potency. Highly potent AMAPs in the colony formation assays included 91U86, an N-methyl-5-benzo(c)carbazole derivative, 773U82, a 3-substituted fluoranthene derivative, and crisnatol (770U82), the 6-substituted chrysene derivative. There was a high frequency of SSBs and DSBs with many analogues, but only SSBs occurred in a concentration-dependent fashion. Using regression analysis, the degree of single-strand damage correlated with cytotoxic potency for the AMAPs, with an R-value of 0.57 (P = 0.04). By gel electrophoresis assays, three clinically tested AMAPs, crisnatol BW 770U82, BW 502U83 and BW 773U82, were shown to inhibit the decatenation of pBR 322 DNA by purified topoisomerase-II (TOPO-II) enzymes. These results suggest that while some active AMAPs, such as crisnatol (BW 770U82), BW 502U83 and BW 773U82, inhibit TOPO-II enzymes, leading to protein-associated SSBs, other mechanisms, which do not involve DNA strand damage, must also contribute to the cytotoxic effects of this class of antitumor compounds. Intercalation has been well documented for these drugs and this may explain some of the growth inhibitory activity of the AMAPs.
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PMID:Correlation of cytotoxicity and protein-associated DNA strand breaks for 2-(arylmethylamino)-1,3-propanediols. 980 65

Advances in the understanding of the cellular and molecular derangements involved in the initiation and progression of multiple myeloma are beginning to be translated into novel therapeutic approaches. The myeloma stem cell has been under intense scrutiny regarding its normal B-cell counterpart. Oncogenes, tumor-suppressor genes, and cell-survival genes have all been found to be dysregulated in some myeloma patients. Growth factors, especially interleukin-6, appear to be critical for disease progression, and interruption of autocrine and paracrine loops has been achieved with resultant inhibition of myeloma cell growth. Mechanisms of drug resistance and the implications of the multidrug resistance phenotype are just beginning to be understood. High-dose therapeutic regimens with autologous peripheral blood stem cell or allogeneic bone marrow rescue are rigorously being studied with an emphasis on exploiting the graft-versus-myeloma effect. Pamidronate, a second-generation bisphosponate, has been shown to be effective at decreasing adverse skeletal events in patients with advanced myeloma. The topoisomerase 1 inhibitor, topotecan, has shown activity in an initial study.
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PMID:Advances in the biology and treatment of multiple myeloma. 991 70

Selection for in vitro drug resistance can result in a complex phenotype with more than one mechanism of resistance emerging concurrently or sequentially. We examined emerging mechanisms of drug resistance during selection with mitoxantrone in the human myeloma cell line 8226. A novel transport mechanism appeared early in the selection process that was associated with a 10-fold resistance to mitoxantrone in the 8226/MR4 cell line. The reduction in intracellular drug concentration was ATP-dependent and ouabain-insensitive. The 8226/MR4 cell line was 34-fold cross-resistant to the fluorescent aza-anthrapyrazole BBR 3390. The resistance to BBR 3390 coincided with a 50% reduction in intracellular drug concentration. Confocal microscopy using BBR 3390 revealed a 64% decrease in the nuclear:cytoplasmic ratio in the drug-resistant cell line. The reduction in intracellular drug concentration of both mitoxantrone and BBR 3390 was reversed by a novel chemosensitizing agent, fumitremorgin C. In contrast, fumitremorgin C had no effect on resistance to mitoxantrone or BBR 3390 in the P-glycoprotein-positive 8226/DOX6 cell line. Increasing the degree of resistance to mitoxantrone in the 8226 cell line from 10 to 37 times (8226/MR20) did not further reduce the intracellular drug concentration. However, the 8226/MR20 cell line exhibited 88 and 70% reductions in topoisomerase II beta and alpha expression, respectively, compared with the parental drug sensitive cell line. This decrease in topoisomerase expression and activity was not observed in the low-level drug-resistant, 8226/MR4 cell line. These data demonstrate that low-level mitoxantrone resistance is due to the presence of a novel, energy-dependent drug efflux pump similar to P-glycoprotein and multidrug resistance-associated protein. Reversal of resistance by blocking drug efflux with fumitremorgin C should allow for functional analysis of this novel transporter in cancer cell lines or clinical tumor samples. Increased resistance to mitoxantrone may result from reduced intracellular drug accumulation, altered nuclear/cytoplasmic drug distribution, and alterations in topoisomerase II activity.
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PMID:Multiple mechanisms confer drug resistance to mitoxantrone in the human 8226 myeloma cell line. 1007 Sep 58

The resistance of several leukaemic and myeloma cell lines (CCRF, L1210, HL-60, KG-1a and RPMI 8226) to VP-16 was found to increase with cell density and to be maximal (3.5- to 39-fold) in plateau phase cell cultures, as measured by clonogenic and MTT assays. Non-transformed confluent Flow 2000 human fibroblasts and Chinese hamster ovary (CHO) cells were also five- and 15-fold resistant to VP-16 respectively. The transition from log to plateau phase was accompanied by a drastic decrease in topoisomerase (topo) IIalpha content in CHO cells and human fibroblasts, while the leukaemic cells maintained constant cellular levels of topo IIalpha and topo IIbeta. However, the nuclear topo IIalpha content was found to decrease as a result of translocation of the enzyme to the cytoplasmic compartment in the leukaemic cells. This was confirmed by subcellular fractionation experiments, Western blotting analyses and immunocytochemistry studies. The quantity of topo IIalpha in plateau phase cytoplasmic fractions ranged from 18% in L1210 cells to 50% in HL-60 and 8226 cells, as measured by both immunoblotting and quantification of the label in immunofluorescent images. The cytoplasmic fraction from plateau phase cells retained topo II catalytic activity, as measured by the decatenation of kinetoplast DNA. The nuclear-cytoplasmic ratio of topo IIalpha may be critical in determining the sensitivity of leukaemic cells to topo II inhibitors. Cytoplasmic trafficking of topo IIalpha was observed in plasma cells obtained from patients with multiple myeloma, and perhaps contributes to drug resistance in this disease.
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PMID:Cell density-dependent VP-16 sensitivity of leukaemic cells is accompanied by the translocation of topoisomerase IIalpha from the nucleus to the cytoplasm. 1069 64

On a series of thirty trephine bone marrow biopsies from patients with multiple myeloma, the authors evaluated expression of markers of cell proliferation or of its blockade (Ki-67, PCNA, topoisomerase IIa, cyclin D-1, AgNOR, and p27kip1) and markers indicating multidrug resistance (P-170 and Bcl-2). Expression of Ki-67 and of topoisomerase IIa was unfrequent. Marked positivity of PCNA was expressed in about one third of cases, negative staining was exceptional. No expression of cyclin D-1 was noted. Positivity of p27kip1 was frequent. P-170 was demonstrated in a small number of cases, Bcl-2 was strongly positive in most cases. The results characterise multiple myeloma as a tumour with low proliferation rate and, simultaneously, with high resistance to apoptosis.
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PMID:[Biological characteristics of multiple myeloma]. 1097 46

Acute leukemia is the most frequent therapy-related malignancy. Together with the increasing use of chemo- and radiotherapy, individual predisposing factors play a key role. Most of secondary leukemias can be divided in two well-defined groups: those secondary to the use of alkylating agents and those associated to topoisomerase inhibitors. Leukemias induced by alkylating agents usually follow a long period of latency from the primary tumour and present as myelodysplasia with unbalanced chromosomal aberrations. These frequently include deletions of chromosome 13 and loss of the entire or of part of chomosomes 5 or 7. The loss of the coding regions for tumor suppressor genes from hematopoietic progenitor cells is a particularly unfavourable event, since the remaining allele becomes susceptible to inactivating mutations leading to the leukemic transformation. The tumorigenic action of topoisomerase inhibitors is on the other hand due to the formation of multiple DNA strand breaks, resolved by chromosomal translocations. Among these, chromosome 11, band q23, where the myeloid-lymphoid leukemia (MLL) gene is located, is often involved. Frequent partners are chromosomes 9, 19 and 4 in the t(9;11), t(19;11) and t(4;11) translocations. Younger age, a mean period of latency of 2 years and monocytic subtypes are characteristic features of this type of leukemia. Among patients at risk for secondary leukemia, those with Hodgkin's disease are the most extensively studied, with the major impact of alkylating agents included in the chemotherapy schedule. The same is true for non-Hodgkin's lymphoma, while in multiple myeloma and acute lymphoblastic leukemia determinants are the dose of melphalan and of epypodophyllotoxin, respectively. Patients with breast, ovarian and testicular neoplasms are also at risk, in particular if trated with the association of alkylating agents and topoisomerase II inhibitors. According to the EBMT registry, in patients with lymphoma treated with high-dose therapy and autologous stem cell transplantation the cumulative risk of inducing leukemia at 5 years is 2.6%. Among treatment options, supportive therapy is indicated in older patients, while allogeneic stem cell transplantation, related or matched-unrelated, is feasible in younger patients. These data indicate the need for the identification of predisposing factors for secondary leukemia. In particular, frequent follow-up of patients at high-risk should be performed and any peripheral blood cytopenia should be considered suspicious. Whenever possible, the exclusion of drugs known to be leukemogenic from the treatment schedules should be considered, especially in young patients.
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PMID:Therapy related leukemias: susceptibility, prevention and treatment. 1137 39

We previously showed that adhesion of myeloma cells to fibronectin (FN) by means of beta1 integrins causes resistance to certain cytotoxic drugs. The study described here found that adhesion of U937 human histiocytic lymphoma cells to FN provides a survival advantage with respect to damage induced by the topoisomerase (topo) II inhibitors mitoxantrone, doxorubicin, and etoposide. Apoptosis induced by a topo II inhibitor is thought to be initiated by DNA damage. The neutral comet assay was used to determine whether initial drug-induced DNA damage correlated with cellular-adhesion-mediated drug resistance. Cellular adhesion by means of beta1 integrins resulted in a 40% to 60% reduction in mitoxantrone- and etoposide-induced DNA double-strand breaks. When the mechanisms regulating the initial drug-induced DNA damage were examined, a beta1 integrin-mediated reduction in drug-induced DNA double-strand breaks was found to correlate with reduced topo II activity and decreased salt-extractable nuclear topo IIbeta protein levels. Confocal studies showed changes in the nuclear localization of topo IIbeta; however, alterations in the nuclear-to-cytoplasmic ratio of topo IIbeta in FN-adhered cells were not significantly different. Furthermore, after a high level of salt extraction of nuclear proteins, higher levels of topo IIbeta-associated DNA binding were observed in FN-adhered cells than in cells in suspension. Together, these data suggest that topo IIbeta is more tightly bound to the nucleus of FN-adhered cells. Thus, FN adhesion by means of beta1 integrins appears to protect U937 cells from initial drug-induced DNA damage by reducing topo II activity secondarily to alterations in the nuclear distribution of topo IIbeta.
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PMID:Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with drug resistance in U937 cells. 1153 27

DNA topoisomerase IIalpha (topo IIalpha) is the target for a number of antineoplastic agents. Down-regulation of this enzyme is one form of drug resistance. Topo IIalpha is also involved in DNA replication and transcription and serves as an indicator of proliferation rate in many human malignancies. This study examines whether topo IIalpha is one of the mechanisms of chemoresistance commonly observed in multiple myeloma (MM) or alternatively, whether topo IIalpha is associated with tumor cell proliferation. Bone marrow (BM) biopsy sections from 72 cases of MM, stratified according to proliferative activity (bromodeoxyuridine uptake), were immunostained for topo IIalpha. Immunoreactivity with an additional marker of drug resistance, glutathione-S-transferase pi, and the proliferation marker Ki-67 were also examined. Topo IIalpha was expressed in 26 (36%) cases and correlated strongly with proliferative activity (P <.001). A role for drug resistance could not be supported, given this strong relationship with proliferation and the finding that glutathione-S-transferase pi expression in 57 (78%) cases was independent of topo IIalpha immunoreactivity. Topo IIalpha was identified in 91 to 100% of highly proliferative tumors, as evaluated by bromodeoxyuridine uptake or Ki-67 reactivity, respectively. Proliferation also correlated with the histologic grade of the MM. Therefore, topo IIalpha immunoreactivity is primarily a marker of cell proliferation in MM and as such is likely to have prognostic significance. Highly proliferative tumors are most likely to be sensitive to chemotherapeutic protocols using anti-topo IIalpha agents.
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PMID:DNA topoisomerase IIalpha in multiple myeloma: a marker of cell proliferation and not drug resistance. 1155 85

Our previous work demonstrated that the Janus kinase (JAK)-Stat3 pathway regulates expression of Bcl-x(L) in the U266 human multiple myeloma cell line and prevents Fas-mediated apoptosis. Inhibition of this pathway by the JAK selective kinase inhibitor AG490 or dominant-negative Stat3 protein results in down-regulation of Bcl-x(L) expression and enhanced sensitivity to Fas-mediated apoptosis. Because Bcl-x(L) has also been implicated in resistance to chemotherapeutic drugs, we investigated whether inhibition of the JAK-Stat3 pathway and subsequent reduction in Bcl-x(L) expression would also enhance cytotoxic drug activity. Contrary to this prediction, pretreatment of U266 myeloma cells with AG490, followed by exposure to topoisomerase II- inhibiting agents, antagonized drug-induced apoptosis. This effect correlated with reduced cyclin D1 expression and cell cycle arrest. The cell cycle arrest following AG490 pretreatment further correlated with reduced mitoxantrone-induced DNA double-strand breaks and reduced cell death, findings consistent with the critical requirement of DNA damage for drug cytotoxicity. These studies demonstrate that inhibition of the JAK-Stat3 pathway can result in paradoxical effects relative to cytotoxic drug response. These paradoxical responses may be explained by the findings that JAK-Stat3 signaling regulates the expression of multiple genes involved in controlling cell proliferation and apoptosis. Thus, understanding the cellular context of inhibiting signal transduction pathways is essential for the design of novel combination therapies for cancer.
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PMID:Inhibition of JAK kinase activity enhances Fas-mediated apoptosis but reduces cytotoxic activity of topoisomerase II inhibitors in U266 myeloma cells. 1175 28

The tumor microenvironment is often overlooked when considering tumor response to chemotherapeutic agents. This environment consists of soluble factors, components of the extracellular matrix as well as cell-cell interactions. Recently, it has become clear that cell-cell and cell-matrix interactions result in cytoskeletal reorganization and the activation of multiple signal transduction pathways that directly influence cell survival, growth and differentiation. Experimental evidence shows that anti-apoptotic pathways initiated by cell adhesion are operative in tumor cells and, furthermore, cause resistance to mechanistically distinct cytotoxics. For hematopoietic tumors, cell adhesion to a single matrix, fibronectin is sufficient to inhibit apoptosis induced by mechanistically distinct cyctotoxics. Adhesion of hematopoietic tumors to this matrix blocks cell cycle progression, and for the human multiple myeloma 8226 cell line adhesion to fibronectin resulted in increased p27kip1 levels, which correlated with cell cycle arrest and drug resistance. A decrease in initial DNA damage induced by topoisomerase II inhibitors has also been observed in adherent hematopoietic tumor cell lines. Further studies investigating the mechanisms of cell adhesion mediated drug resistance may reveal novel targets directed at the reversal of de novo drug resistance.
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PMID:Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies. 1183 46

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