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)

Three genes encoding enzymes involved in the biosynthesis of pyrimidines have been found to constitute an operon in Lactococcus lactis. Two of the genes are the well-known pyr genes pyrDb and pyrF, encoding dihydroorotate dehydrogenase and orotidine monophosphate decarboxylase, respectively. The third gene encodes a protein which was shown to be necessary for the activity of the pyrDb-encoded dihydroorotate dehydrogenase; we propose to name the gene pyrK. The pyrK-encoded protein is homologous to a number of proteins which are involved in electron transfer. The lactococcal pyrKDbF operon is highly homologous to the corresponding part of the much-larger pyr operon of Bacillus subtilis. orf2, the pyrK homolog in B. subtilis, has also been shown to be necessary for pyrimidine biosynthesis (A. E. Kahler and R. L. Switzer, J. Bacteriol. 178:5013-5016, 1996). Four genes adjacent to the operon, i.e., orfE, orfA, orfC, and gidB, were also sequenced. Three of these were excluded as members of the pyr operon by insertional analysis (orfA) or by their opposite direction of transcription (orfE and gidB). orfC, however, seems to be the distal gene in the pyrKDbF-orfC operon.
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PMID:Sequence analysis and identification of the pyrKDbF operon from Lactococcus lactis including a novel gene, pyrK, involved in pyrimidine biosynthesis. 875 67

EctoATPases are extracellular membrane-bound enzymes that catalyze the hydrolysis of the gamma phosphate from ATP. EctoATPase is expressed by activated and immortalized Epstein-Barr virus-transformed human peripheral blood B lymphocytes and murine B cell hybridomas. By contrast, ectoATPase activity is not expressed on nontransformed human peripheral blood B lymphocytes, murine spleen cells, or murine myeloma cells. The K(m) for ATP for the B cell ectoATPases ranged from 5 to 77 microM; the Vmax ranged from 48 to 129 pmol/ min/10(4) cells. The enzyme required Mg2+ for maximal activity with little dependence on Ca2+. ADP and purine and pyrimidine nucleoside triphosphates were competitive inhibitors of the catalytic reaction. A putative ectoATPase protein has been identified by Western blot analysis of membrane proteins from the immortalized B cells. Under reducing conditions, antiectoATPase antibodies cross-reacted with a 66-kDa protein from murine B cell hybridoma membranes. By contrast a 200-kDa protein from the B cell hybridoma membranes cross-reacted with the antibodies under nonreducing conditions, suggesting a disulfide-linked trimer. The antibodies also cross-reacted with a 66-kDa protein from human B cell membranes under reducing conditions, but did not cross-react with membrane proteins under nonreducing conditions. This suggests that the antibody epitope(s) recognized on the reduced human protein is masked under nonreducing conditions. Thus, this work demonstrates: (1) that ectoATPase may serve as a marker for B cell activation; and (2) mammalian and avian ectoATPases have conserved interspecies immunological epitopes and kinetic properties.
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PMID:Identification and partial characterization of ectoATPase expressed by immortalized B lymphocytes. 912 71

Multiple myeloma (MM) is an incurable disease despite an initial response-rate of >60% with conventional or high-dose chemotherapy using glucocorticosteroids (i.e. dexamethasone), or alkylating agents (i.e. melphalan). Although these agents are capable of inducing complete remission (CR) in >50% of MM patients, resistance develops rapidly, in >90% of patients, within 2 years of treatment. Therefore, there is a need for new drugs for the treatment of relapsing and refractory MM patients. Gemcitabine (GEM) is a pyrimidine analog that blocks DNA synthesis, whereas, paclitaxel (TAX) is a mitotic spindle poison that promotes microtubular aggregation. Since it appears that these two drugs have different cellular targets, we examined the effect of each drug individually for several parameters and for possible synergy. We studied the cytotoxic effect of TAX and GEM on MM cells expressing varying levels of the antiapoptotic protein bcl-2, which is overexpressed in the majority of myeloma cell from MM patients. We found that both drugs are cytotoxic by inducing apoptosis, however, the extent of apoptosis with TAX, but not with GEM was dependent on the levels of bcl-2 expression. We further investigated the effect of TAX and GEM on the cell cycle distribution and on the levels of bcl-2. The results indicate that the two drugs have different modes of action with respect to each parameter tested. TAX induced arrest of the cells in the G2/M phase of the cell cycle, regardless of bcl-2 levels, however, apoptosis was induced in mitotic cells expressing relatively low levels of bcl-2. In contrast, GEM caused apoptosis of cells in the S-phase, regardless of level of bcl-2 expression. A major difference between TAX and GEM was in their effects on the levels of bcl-2. Whereas, TAX induced an early downregulation of bcl-2 (only in the cells with relatively low levels of bcl-2), treatment with GEM did not affect bcl-2 levels. The effects of TAX on both the cell cycle and bcl-2 were detected very early (4-8 h) and preceded the onset of apoptosis. GEM and TAX act synergistically, at low doses (IC50 of 0.5 microM for GEM and 0.025 microM for TAX), to effectively kill bcl-2 overexpressing cells that are resistant to higher doses (0.25 microM) of TAX alone. Therefore, we have initiated a phase II clinical trial of TAX and GEM for MM patients refractory to current therapy.
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PMID:Bcl-2 overexpression is associated with resistance to paclitaxel, but not gemcitabine, in multiple myeloma cells. 973 15

Gemcitabine is a pyrimidine analogue that showed significant activity in solid malignancies. Gemcitabine acts by inhibiting DNA synthesis through chain termination and ribonucleotide reductase inhibition. During initial phase I and II studies, gemcitabine had a low toxicity profile and was well tolerated as a single agent and in combination therapy. Recently, there has been more interest in studying the activity of gemcitabine in hematologic malignancies. Gemcitabine demonstrated good activity in refractory Hodgkin disease patients, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and acute leukemias. There is a preponderance of evidence on the activity of gemcitabine in vitro in myeloma and leukemic cell lines. The activity of gemcitabine in these disorders will pave the way for incorporating this agent into the early phases of therapy.
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PMID:Gemcitabine in hematologic malignancies. 1167 93

In this study, we analyzed the targeting of the somatic hypermutation (SHM) mechanism at specific hotspot sequence motifs in the V(H) and Vkappa genes of 10 follicular lymphoma (FL) cases and the Vkappa and Vlambda genes of 11 kappa- and six lamda-light chain expressing multiple myeloma (MM) cases. These sequences were analyzed for targeting of specific motifs, ie certain highly mutable trinucleotides (3-NTPs), the tetranucleotide (4-NTP) RGYW and its complementary, WRCY (where R = purine, Y = pyrimidine and W = A or T). Comparisons were carried out between mutation frequencies in RGYW vs WRCY and the incidence of mutations in complementarity determining region (CDR)-1 vs CDR2 vs CDR3. Statistically significant differences were obtained when comparing: (1) the ratio of mutations in 4-NTPs (RGYW, WRCY, RGYW+WRCY)/mutations in the whole V sequence in MM-Vkappa vs MM-Vlamda; (2) the total number of mutated 4-NTPs in MM-Vkappa vs FL-Vkappa; (3) the number of mutated RGYW 4-NTPs in MM-Vkappa vs FL-Vkappa and FL-V(H) vs FL-Vkappa; (4) the number of mutated WRCY 4-NTPs in MM-Vkappa vs FL-Vkappa (P= 0.006) and FL-V(H) vs FL-Vkappa; (5) the targeting of RGYW vs WRCY in the CDRs of FL-V(H) genes. Similar results (regarding statistical significance) were obtained when undertaking intergroup comparisons for 3-NTPs. These findings conform well with relevant data derived from normal peripheral B cells. The differences observed in favor of 4-NTP (RGYW and WRCY) targeting in FL-V(H) vs FL-Vkappa and MM-Vkappa vs FL-Vkappa may implicate differences in the evolution of SHM coupled with selection in different stages of B cell ontogeny. Several explanations can be offered for the fact that hotspot sequences were not always targeted by SHM in FL and MM: (1) other unrecognized motifs may be targets of SHM; (2) 'inappropriately' introduced mutations were fixed and propagated by the neoplastic process; (3) certain FL and MM cases might have lost their ability to correct mutations introduced in classic hotspots due to deficient mismatch-repair (MMR) mechanisms; conversely, in other cases with intact MMR function, the hotspot to non-hotspot targeting of somatic hypermutation is balanced.
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PMID:Somatic hypermutation targeting to intrinsic hotspots of immunoglobulin genes in follicular lymphoma and multiple myeloma. 1168 20

Gemcitabine is a pyrimidine nucleoside analog with antitumor activity against solid tumor malignancies and leukemia. We evaluated its activity as a single agent and combining it with cisplatin in relapsed-refractory multiple myeloma (MM). Sixteen patients with advanced MM received intravenous gemcitabine 1250 mg/mq (days 1, 8 and 15) as a single agent for a total of 3 monthly courses. The responders received another three courses, and the non-responders received three courses of gemcitabine 1000 mg/mq (days 1, 8 and 15) plus cisplatin 80 mg/mq (day 1). No grade 4 hematological toxicity was seen after gemcitabine treatment, whereas > or = 3 grade neutropenia and thrombocytopenia were seen in 21 and 13% of the gemcitabine-cisplatin infusions, respectively. Non-hematological toxicity was negligible for both the regimens. After three courses of gemcitabine as a single agent, th e response rate was 31% (1 complete response, 1 partial response and 3 minimal response). Eight patients (50%) achieved stable disease and 3 (19%) had disease progression. Ten patients received gemcitabine-cisplatin and were evaluable for the response. Two patients progressed, four maintained stable disease whereas four patients, unresponsive to gemcitabine, obtained a response (3 partial response and 1 minimal response). With a median follow-up of 13 months (range 8-17.5), 7 patients (44%) died, 5 (31%) had disease progression, 1 (6%) relapsed, 1 was still in partial response (+11 months) and 2 (13%) had a stable disease. Median time to treatment failure (TTF) was 8 months (CI95%: 7.6-8.4) and median overall survival (OS) was 16 months (CI95%: 10-22). These results showed that gemcitabine and gemcitabine-cisplatin were feasible regimens and well tolerated in advanced relapsed-refractory MM. The response rates, the TTF and OS were similar to other salvage chemotherapy regimens; nevertheless, the quality of response was modest particularly after gemcitabine alone. Better results might be obtained combining gemcitabine with other chemotherapy compounds or with biologically based therapies.
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PMID:Gemcitabine alone or combined with cisplatin in relapsed or refractory multiple myeloma. 1215 96

The objective of this study was to determine potential mechanisms of apoptotic activity of gemcitabine, a pyrimidine nucleoside analogue, in the MM1.S multiple myeloma (MM) cell line. A MM cell line that is sensitive to glucocorticoids (MM1.S) was used for this study. Immunoblotting analysis, cell cycle assays, and annexin V staining were performed to determine whether gemcitabine induced apoptosis in this model. Furthermore, we attempted to delineate the apoptotic pathway by measuring caspase-8 and -9 activity using fluorometric assays. Loss of mitochondrial membrane potential was measured by flow cytometry. Gemcitabine treatment caused apoptosis in MM cell lines as measured by an increase in DNA cleavage, an increase in annexin V binding, a decrease in the mitochondrial membrane potential, and activation of caspase activity. Furthermore, cleavage of the caspase substrate poly(ADP-ribose) polymerase and caspase-3 activation were documented as early as 8 h after treatment with gemcitabine. Caspase-8 and -9 were activated by gemcitabine treatment in this cell line, suggesting several mechanisms of action including death receptor pathway and mitochondrial damage. The addition of interleukin 6 to MM1.S cells treated with gemcitabine offered no protection against gemcitabine-induced cell death. Gemcitabine induced apoptosis in the MM1.S cell line, and its activity required caspase activation. There is a suggestion that mitochondrial integrity is being affected with gemcitabine in this system. Gemcitabine acts independently of interleukin 6, suggesting potential important therapeutic implications in MM patients.
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PMID:Caspase activation is required for gemcitabine activity in multiple myeloma cell lines. 1247 3

The in vitro cytotoxic activity profile of nine novel phenylarsonic acid (CAS 98-05-5, PAA) compounds against 17 human cancer cell lines including (a) ovarian cancer cell lines ES-2, PA-1, CAOV-3, OVCAR-3, (b) testicular cancer cell lines Ntera-2, Tera-2, N2NICP, 833K, and 64CP, (c) multiple myeloma cell lines ARH77, HS-Sultan, RPMI-8226, and U266, and (d) acute lymphoblastic leukemia (ALL) cell lines NALM-6, MOLT-3, ALL-1, and RS4; 11, was determined by the MTT assay. The lead compounds, 2-methylthio-4-[(4'-aminophenylazo)-phenylarsonic acid] pyrimidine (PHI-370) and 2-methylthio-4-(4'-phenylarsonic acid)-aminopyrimidine (PHI-380) caused apoptotic death in all 17 cancer cell lines at low micromolar concentrations, as documented by TUNEL assays and confocal laser scanning microscopy. PHI-380 was also tested and found to be very active against primary tumor cells isolated from surgical biopsy specimens of 14 patients with therapy-refractory non-small cell lung cancer, breast cancer, colon cancer, lymphoma, hepatoblastoma, or Wilm's tumor as well. Because of their broad-spectrum and potent anticancer activity and ability to induce apoptosis in primary tumor cells from therapy-refractory cancer patients, PAA compounds such as PHI-370 and PHI-380 may provide the basis for effective salvage regimens for patients with recurrent cancer.
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PMID:Phenylarsonic acid compounds with broad-spectrum and potent cytotoxic activity against human cancer cells. 1287 14

Ribonucleotide reductase (RR) is the enzyme that catalyses the rate-limiting step in DNA synthesis, the production of deoxynucleotides. RR activity is markedly elevated in tumour tissue and is crucial for cell division. It is therefore an excellent target for cancer chemotherapy. This study examined the anti-myeloma activity of Didox (3,4-Dihydroxybenzohydroxamic acid), a novel RR inhibitor (RRI). Our data showed that Didox induced caspase-dependent multiple myeloma (MM) cell apoptosis. Didox, unlike other RRIs that mainly target the pyrimidine metabolism pathway, targets both purine and pyrimidine metabolism pathways in MM, as demonstrated by transcriptional profiling using the Affymetrix U133A 2.0 gene chip. Specifically, a >or=2-fold downregulation of genes in these anabolic pathways was shown as early as 12 h after exposure to Didox. Furthermore, apoptosis was accompanied by downregulation of bcl family proteins including bcl-2, bcl(xl), and XIAP. Importantly, RR M1 component transcript was also downregulated, associated with decreased protein expression. Genes involved in DNA repair mechanisms, specifically RAD 51 homologue, were also downregulated. As Didox acts on MM cells by inhibiting DNA synthesis and repair, combination studies with melphalan, an agent commonly used in MM, were performed. A strong in vitro synergism was shown, with combination indices of <0.7 as determined by the Chou-Talalay method. These studies therefore provide the preclinical rationale for evaluation of Didox, alone and in combination with DNA-damaging agents, to improve patient outcome in MM.
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PMID:Didox, a ribonucleotide reductase inhibitor, induces apoptosis and inhibits DNA repair in multiple myeloma cells. 1692 73

Multiple myeloma (MM) is a B-cell malignancy characterized by accumulation of monoclonal plasma cells in the bone marrow (BM). Despite recent advances in the treatment, MM represents an incurable disease for which development of new therapies is required. We report the antimyeloma effect of NVP-AEW541, a small molecule that belongs to the pyrrolo[2,3-d]pyrimidine class, identified as a selective inhibitor of the insulin-like growth factor-I receptor (IGF-IR) in vitro kinase activity. NVP-AEW541 had a potent cytotoxic effect on fresh cells and in a murine MM model. NVP-AEW541 partially abrogated the proliferative advantage conferred by the coculture with BM stromal cells and the presence of growth factors produced by the BM microenvironment. In addition, NVP-AEW541 potentiated the action of drugs, such as bortezomib, lenalidomide, dexamethasone or melphalan. Moreover the triple combination of NVP-AEW541, dexamethasone and bortezomib resulted in a significant increase in growth inhibition. Mechanistic studies indicated that NVP-AEW541 provoked a marked cell cycle blockade accompanied by pRb downregulation. Interestingly, NVP-AEW541 increased the levels of p27 associated with a reduction in the CDK2 activity. Finally, NVP-AEW541 induced cell death through caspase-dependent and -independent mechanisms. All these data, suggest the potential effect of IGF-IR kinase inhibitors as therapeutic agents for MM patients.
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PMID:The insulin-like growth factor-I receptor inhibitor NVP-AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells. 1834 34


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