Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug resistance is one of the most significant impediments in the treatment of hematological malignancies. There have been a number of studies on the incidence of P-GP expression in tumor cells or tissues, where detectable level of P-GP has been found in all types of hematological malignancies. P-GP expression and significance in the patients varies widely between reported studies on patients with different ages and different disease types. Some of this validation can be accounted for by the threshold used to consider a sample positive for P-GP. However, mdr-1 is likely important in determining therapeutic outcome in patients with AML, NHL, and MM, although there is a suggestion of a different "behavior" between adult and childhood AML. In contrast, the significant prognostic association with expression of MRP and LRP is not consistent with disease types and disease stages. Clinical trials of modulation of MDR have been limited by following major factors. One is inability of achieving adequate blood levels of the modulator to reverse MDR, and the other is presence of other resistance mechanisms in addition to P-GP. The fact that P-GP modulators alter the pharmacokinetics of anti-cancer drugs can potentially increase toxicities if the dose of anticancer drugs is not appropriately reduced. Recently, MDR modulators such as valspodar have demonstrated substantial inhibition of P-GP. In this presentation, a number of characteristics in VCR-resistant cells are reported. We demonstrate that acquisition of MDR or recovery from MDR phenotypes differ in one cell type to another, a marked correlation between P-GP and susuceptibility to oxygen radicals, and altered gene expression of cell membrane antigen and apoptosis cascade genes. The efficacy of immunotherapies depends on the altered or unchanged target molecules of MDR cells. Thus, immunotherapies or reversal agents that aim at these substances in tumor cells should be useful to overcome MDR phenotypes.
 ...
PMID:Biology and modulation of multidrug resistance (MDR) in hematological malignancies. 1243 Sep 27

Among the 25 bis(cyclopentadienyl)vanadium(IV) and 14 oxovanadium(IV) compounds synthesised and evaluated for anticancer activity, bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (metvan) was identified as the most promising multitargeted anticancer vanadium complex with apoptosis-inducing activity. At nanomolar and low micromolar concentrations, metvan induces apoptosis in human leukaemia cells, multiple myeloma cells and solid tumour cells derived from breast cancer, glioblastoma, ovarian, prostate and testicular cancer patients. It is highly effective against cisplatin-resistant ovarian cancer and testicular cancer cell lines. Metvan is much more effective than the standard chemotherapeutic agents dexamethasone and vincristine in inducing apoptosis in primary leukaemia cells from patients with acute lymphoblastic leukaemia, acute myeloid leukaemia or chronic acute myeloid leukaemia. Metvan-induced apoptosis is associated with a loss of mitochondrial transmembrane potential, the generation of reactive oxygen species and depletion of glutathione. Treatment of leukaemia cells from acute lymphoblastic leukaemia, acute myeloid leukaemia and chronic acute myeloid leukaemia patients with metvan inhibits the constitutive expression as well as the gelatinolytic activities of matrix metalloproteinase-9 and -2. Treatment of human malignant glioblastoma and breast cancer cells with metvan at concentrations > 1 microM is associated with a nearly complete loss of the adhesive, migratory and invasive properties of the treated cancer cell populations. Metvan shows favourable pharmacokinetics in mice and does not cause acute or subacute toxicity at the dose levels tested (12.5 - 50 mg/kg). Therapeutic plasma concentrations > or = 5 microM, which are highly cytotoxic against human cancer cells, can be rapidly achieved and maintained in mice for at least 24 h after intraperitoneal bolus injection of a single 10 mg/kg non-toxic dose of metvan. Metvan exhibits significant antitumour activity, delays tumour progression and prolongs survival time in severe combined immunodeficient mouse xenograft models of human malignant glioblastoma and breast cancer. The broad spectrum anticancer activity of metvan together with favourable pharmacodynamic features and lack of toxicity warrants further development of this oxovanadium compound as a new anticancer agent. Metvan could represent the first vanadium complex as an alternative to platinum-based chemotherapy.
 ...
PMID:Metvan: a novel oxovanadium(IV) complex with broad spectrum anticancer activity. 1245 42

The majority of immunotherapy-based gene therapy protocols consist of ex vivo gene transfer in tumor cells. To prevent further in vivo growth, modified cells must be irradiated before reinjection into patients. The present study examines the effects of gamma-irradiation on transgene expression in transduced leukemic cells. Human and murine leukemic cells were transfected with retroviral vectors or plasmids carrying beta-galactosidase, GM-CSF or CD80 genes. Fresh leukemic cells from patients with acute myeloid leukemia (AML) were transfected with AdZ.F(pK7) adenoviral vector. gamma-irradiation at various lethal doses enhanced transgene expression in leukemic cell lines and fresh AML cells when the gene of interest was under CMV promoter but not when SV40 promoter was used. Oxidative stress also enhanced transgene expression and both irradiation and oxidative stress effects were inhibited by addition of N-acetyl-L-cysteine, a thiol anti-oxidant, indicating the involvement of reactive oxygen species. Transgene expression was also enhanced in vivo 48 and 120 h after subcutaneous injection of irradiated leukemic cells in syngeneic mice. These results show that a cell vaccine protocol using ex vivo gene transfer of transduced cells might be feasible in acute leukemia even if leukemic cells must be irradiated at lethal doses prior to reinjection to patients.
 ...
PMID:Gamma-irradiation enhances transgene expression in leukemic cells. 1257 30

Effects of the histone deacetylase (HDAC) inhibitor MS-275 have been examined in human leukemia and lymphoma cells (U937, HL-60, K562, and Jurkat) as well as in primary acute myelogenous leukemia blasts in relation to differentiation and apoptosis. MS-275 displayed dose-dependent effects in each of the cell lines. When administered at a low concentration (e.g., 1 micro M), MS-275 exhibited potent antiproliferative activity, inducing p21(CIP1/WAF1)-mediated growth arrest and expression of differentiation markers (CD11b) in U937 cells. These events were accompanied by an increase in hypophosphorylated retinoblastoma protein and down-regulation of cell cycle-related proteins including cyclin D1. However, at higher concentrations (e.g., 5 micro M), MS-275 potently induced cell death, triggering apoptosis in approximately 70% of cells at 48 h. In contrast to other HDAC inhibitors such as apicidin, the extrinsic, receptor-mediated pathway played a minimal role in MS-275 lethality. However, MS-275 potently induced a very early (e.g., within 2 h) increase in reactive oxygen species (ROS), followed by the loss of mitochondrial membrane potential (Delta psi(m)) and cytosolic release of cytochrome c. These events culminated in activation of the caspase cascade, manifested by poly(ADP-ribose) polymerase, p21(CIP1/WAF1), p27(KIP), Bcl-2, and retinoblastoma protein degradation. MS-275 exposure also resulted in diminished expression of cyclin D1 and the antiapoptotic proteins Mcl-1 and XIAP. Administration of the free radical scavenger L-N-acetylcysteine blocked MS-275-mediated mitochondrial injury and apoptosis, suggesting a primary role for ROS generation in MS-275-associated lethality. Lastly, U937 cells stably expressing a p21(CIP1/WAF1) antisense construct were significantly more sensitive to MS-275-mediated apoptosis than controls, but they were impaired in their differentiation response. Together, these findings demonstrate that MS-275 exerts dose-dependent effects in human leukemia cells, i.e., p21(CIP1/WAF1)-dependent growth arrest and differentiation at low drug concentrations and a marked induction of ROS, mitochondrial damage, caspase activation, and apoptosis at higher concentrations.
 ...
PMID:The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. 1283 53

The biological effects of epicuticular substances in farinose exudates accumulated on inflorescence shafts and calyces of Primula denticulata on human acute myeloid leukemia cells (HL-60) were analyzed. The crude material possessed little antioxidative capacity but strong cytostatic properties. Some of its known components (5-hydroxyflavone, 2'-hydroxyflavone, 5,2'-dihydroxyflavone, and 5,8-dihydroxyflavone) were further tested to identify the biologically active compounds. The effects of these flavones on cell cycle progression, mitochondrial membrane potential, and reactive oxygen species have been investigated by flow cytometry. The flavonol quercetin was included in the study as reference compound because of its known cytostatic properties and its activity as radical scavenger. Compared to quercetin the flavones induced little apoptosis (up to 40 microM), but despite their low toxicity, the Primula flavonoids possessed strong cytostatic properties even at low concentrations. The cell cycle distribution showed a characteristic time-dependent shift, giving evidence of a generally short-lived effect of the test compounds in the exposed cells. The antioxidative properties quantified according to two different methods correlated with the number of hydroxyl groups. Whereas quercetin strongly affected the mitochondrial membrane potential, none of the Primula flavones showed a comparable effect.
 ...
PMID:Biological effects of epicuticular flavonoids from Primula denticulata on human leukemia cells. 1473 2

Chemotherapeutic drugs kill cancer cells mainly by direct cytotoxicity, but they might also induce a stronger host immune response by causing the tumor to produce costimulatory cell surface molecules like CD80. We previously reported that in myeloid leukemic cells, gamma-irradiation induced CD80 expression. In this study, we show that cytosine arabinoside (Ara-C), even at low doses, induced CD80 expression in vitro in mouse DA1-3b leukemic cells, by a mechanism that involved reactive oxygen species. In vivo experiments in the mouse DA1-3b/C3H whole-animal acute myeloid leukemia (AML) model showed that injection of Ara-C induced expression of CD80 and CD86, and decreased expression of B7-H1, indicating that chemotherapy can modify costimulatory molecule expression in vivo, in a way not necessarily observed in vitro. Mouse leukemic cells exposed in vivo to Ara-C were more susceptible to specific cytotoxic lymphocyte (CTL)-mediated killing. Ara-C also induced CD80 or CD86 expression in 14 of 21 primary cultured human AML samples. In humans being treated for AML, induction chemotherapy increased CD86 expression in the leukemic cells. These findings indicate possible synergistic strategies between CTL-based immunotherapy and chemotherapy for treatment. They also suggest an additional mechanism by which chemotherapy can eradicate AML blasts.
 ...
PMID:Cytosine arabinoside induces costimulatory molecule expression in acute myeloid leukemia cells. 1515 66

The purpose of this study was to investigate the adaptive mechanisms of hydrogen peroxide-supersensitive AML cells against the reactive oxygen species (ROS). Their scavenging capacity against ROS was determined using a fluorometric probe in the doxorubicin-resistant AML-2/DX100 cell characterized by the down-regulation of catalase. AML-2/DX100 cells had more scavenging capacity against endogenous pro-oxidants than did the parental cells AML-2/WT, suggesting that an anti-oxidant adaptation against ROS occurred. cDNA microarrays for 8000 human genes revealed that among 21 anti-oxidant genes, each four gene was up- and down-regulated more than 1.5-fold in AML-2/DX100 compared with AML-2/WT. The mRNA expression of glutathione S-transferase Pi, peroxiredoxin 2, thioredoxin 2, and glutaredoxin was elevated whereas that of peroxiredoxin 3, metallothionein-1F, superoxide dismutase 2, and thioredoxin reductase 1 was depressed. The result indicates that the down-regulation of certain anti-oxidant mechanisms can be compensated for by the up- and down-regulation of the other anti-oxidant mechanisms.
 ...
PMID:Anti-oxidant adaptation in the AML cells supersensitive to hydrogen peroxide. 1515 39

Increased microvessel density (MVD) has been observed in the bone marrow (BM) of patients with multiple myeloma (MM), acute lymphoblastic leukaemia, acute myeloid leukaemia, and myelodysplastic and myeloproliferative syndrome. The MVD is the net result of cumulative phases of angiogenesis and angio-regression and is as such not an indicator of the ongoing angiogenesis at the time of biopsy. There is, therefore, a need for additional methods that allow the estimation of ongoing angiogenesis. Double immunostainings for CD34 and Ki-67 can be used on paraffin-embedded tissue to determine the endothelial proliferation fraction. The BM endothelial cells, as a component of the BM stroma, have a close interaction with the malignant cells. In MM, for example, they are involved in the specific homing and are a source of paracrine growth factors. Targeting the BM microvessels will not only influence the nutrient and oxygen supply, but will in addition reduce the growth stimuli provided by the EC.
 ...
PMID:Angiogenesis and the role of bone marrow endothelial cells in haematological malignancies. 1516 56

Recent studies have described malignant stem cells as central to the initiation, growth, and potential relapse of acute and chronic myelogenous leukemia (AML and CML). Because of their important role in pathogenesis, rare and biologically distinct leukemia stem cells (LSCs) represent a critical target for therapeutic intervention. However, to date, very few agents have been shown to directly target the LSC population. The present studies demonstrate that parthenolide (PTL), a naturally occurring small molecule, induces robust apoptosis in primary human AML cells and blast crisis CML (bcCML) cells while sparing normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays, as well as stem cells using the nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model, show that PTL also preferentially targets AML progenitor and stem cell populations. Notably, in comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The molecular mechanism of PTL-mediated apoptosis is strongly associated with inhibition of nuclear factor kappa B (NF-kappaB), proapoptotic activation of p53, and increased reactive oxygen species (ROS). On the basis of these findings, we propose that the activity of PTL triggers LSC-specific apoptosis and as such represents a potentially important new class of drugs for LSC-targeted therapy.
 ...
PMID:The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. 1568 34

Interactions between the novel histone deacetylase inhibitor LAQ824 and the cyclin-dependent kinase inhibitor roscovitine were examined in human leukemia cells. Pretreatment (24 hours) with a subtoxic concentration of LAQ824 (30 nmol/L) followed by a minimally toxic concentration of roscovitine (10 micromol/L; 24 hours) resulted in greater than additive effects on apoptosis in U937, Jurkat, and HL-60 human leukemia cells and blasts from three patients with acute myelogenous leukemia. These events were associated with enhanced conformational changes in Bax; mitochondrial release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor; and a marked increase in caspase activation. LAQ824/roscovitine-treated cells displayed caspase-dependent down-regulation of p21(CIP1) and Mcl-1 and a pronounced caspase-independent reduction in X-linked inhibitor of apoptosis (XIAP) expression. The lethality of this regimen was significantly attenuated by ectopic expression of XIAP, a nuclear localization signal-defective p21(CIP1) mutant, Mcl-1, and Bcl-2. Combined exposure to LAQ824 and roscovitine resulted in a significant reduction in XIAP mRNA levels and diminished phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Notably, roscovitine blocked LAQ824-mediated differentiation. Finally, LAQ824 and roscovitine individually and in combination triggered an increase in generation of reactive oxygen species; moreover, coadministration of the free radical scavenger N-acetylcysteine prevented LAQ824/roscovitine-mediated mitochondrial injury and apoptosis. Collectively, these findings suggest that combined treatment of human leukemia cells with LAQ824 and roscovitine disrupts maturation and synergistically induces apoptosis, lending further support for an antileukemic strategy combining novel histone deacetylase and cyclin-dependent kinase inhibitors.
 ...
PMID:Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells. 1627 99


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>