Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycyrrhizin (GL), a plant extract, has been evaluated for its inhibitory effect on HIV replication in vitro and for its improvement of clinical symptoms in HIV-infected patients. In this study, we used GL in a murine AIDS model (MAIDS) to evaluate these effects. C57BL/6 mice were inoculated with LP-BM5 murine leukemia virus to cause MAIDS. Treatment with GL supplemented with glycine and cysteine (Stronger Neo-Minophagen C, SNMC) was then begun on day 0 or 4 wks after virus inoculation. SNMC was administered three times a week for up to 19 wks. Immunological abnormalities were monitored with respect to the surface phenotype identified by two-color staining for CD3 and IL-2 receptor beta-chain. All mice infected with the virus alone developed MAIDS and died by 14 wks after infection. The immunopathogenesis was estimated to be an abnormal expansion of intermediate CD3 cells (i.e., extrathymic T cells) as well as other types of lymphocytes. SNMC did not change the total mortality rate. However, some mice that began the treatment on day 0 or 4 wks after infection survived 3 wks longer. Splenomegaly and lymphadenopathy in such mice were suppressed. These mice showed normal phenotypic features and normal responses to Con A. These results suggest that SNMC is effective in some MAIDS mice in preventing the progression of disease. When lymphocytes isolated from the liver, spleen and lymph nodes of diseased mice were cultured in vitro, they showed a spontaneous proliferation. Interestingly, such proliferation was inhibited by addition of liver lymphocytes, but not splenic lymphocytes, obtained from normal or SNMC-treated mice. Since liver lymphocytes contains intermediate CD3 cells with autoreactivity, they may possibly suppress the progression of disease.
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PMID:Therapeutic effects of glycyrrhizin in mice infected with LP-BM5 murine retrovirus and mechanisms involved in the prevention of disease progression. 901 40

High efficiency retroviral-mediated gene transfer to rhesus CD4+ peripheral blood lymphocytes (PBL) was accomplished using an optimized transduction protocol using a gibbon ape leukemia virus (GaLV) envelope-containing packaging cell line PG13. Engineered CD4+ PBL were administered to three nonmyeloablated animals in three or four separate infusions over 9 months. Polymerase chain reaction (PCR) demonstrated in vivo reconstitution of the genetically engineered CD4+ PBL at levels between 1% and 10% of the circulating leukocytes. This level of gene marking indicates that up to 30% of endogenous circulating CD4+ cells can be genetically engineered. The high levels of marked lymphocytes persist for the first 3 weeks following reinfusion then decline to < or = 0.1% over the next 21 weeks. Lymph node (LN) biopsies were performed to determine if the engineered CD4+ lymphocytes could traffic to lymphoid tissues. Marked lymphocytes were detected in LN biopsies 100 days following reinfusion of the transduced cells. Expression of retroviral vector-derived sequences was detected by reverse transcriptase (RT)-PCR analysis from CD4-enriched lymphocytes that were activated by culturing in the presence of recombinant interleukin-2 (rlL-2). A humoral immune response to fetal bovine serum (FBS) was detected in all animals following the second administration of the culture expanded CD4+ lymphocytes. No antibody response was detected to the neomycin-resistance (Neo(R)) transgene, the murine retroviral group-specific antigen (gag), or GaLV envelope (env) proteins.
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PMID:Efficient in vivo marking of primary CD4+ T lymphocytes in nonhuman primates using a gibbon ape leukemia virus-derived retroviral vector. 905 20

Tumor necrosis factor alpha (TNF-alpha), an important cytokine produced mainly by activated macrophages, plays a critical role in certain physiological immune systems. But it causes severe damage to the host when produced in excess. Therefore, TNF-alpha can be regarded to possess both favorable and unfavorable effects. These pleiotropic effects indicated that TNF-alpha production-enhancers in some cases and TNF-alpha production-inhibitors in other cases would be useful as biological response modifiers (BRMs) under various circumstances. A possible lead compound is thalidomide, which had been used as a hypnotic/sedative agents but was withdrawn from the market because of it's teratogenicity. Thalidomide is a specific inhibitor of TNF-alpha production, and this effect has been shown to be useful for the treatment of various immunodiseases. Recently, we found that the regulation of TNF-alpha production by thalidomide and related hthalimides was both inducer-specific and cell-type-specific, i.e., (I) the compounds enhance 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced TNF-alpha production by HL-60 cells, while they inhibit TPA-induced TNF-alpha production by another human leukemia cell line THP-1, and (II) the compounds inhibit TNF-alpha production both by HL-60 and THP-1 cells when the cells are stimulated with okadaic acid. We also found that in a optically active phthalimide analogues of thalidomide the inducer specific bi-directional regulation of TNF-alpha production is separated. This implies that the target molecule(s) of the two systems are different each other.
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PMID:[Novel biological response modifiers: phthalimides with TNF-alpha production regulating activity]. 908 26

Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia/lymphoma (ATLL). HTLV Tax, the viral transcriptional activator, can activate a variety of cellular genes. HTLV-mediated T-cell transformation, however, may involve additional viral proteins expressed from singly- as well as doubly-spliced viral mRNA. To determine the combined effect of these viral proteins on cellular gene expression in Jurkat T-cells, we derived stable transfectants that constitutively express the HTLV-I pX and env regions (J3.9). J3.9 cells show substantially increased mRNA levels of egr-1 and c-jun but no induction of either CD25 or GM-CSF by Northern blotting. This pattern corresponded to the activation of an egr-1 but not a GM-CSF promoter-driven reporter construct in transient gene expression assays. In DNA electrophoretic mobility shift assays (EMSA), nuclear extract from J3.9 cells has significantly increased binding to CRE and SRE but not nuclear factor kappa B (NF kappa B) DNA oligos, as compared to J-Neo cell extract. These results suggest that low level expression of pX and env region gene products in Jurkat T-cells stimulates persistent activation of CRE- and SRE- but not NF kappa B-induced cellular genes.
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PMID:Constitutive expression of the HTLV-I pX and env regions in Jurkat T-cells induces differential activation of SRE, CRE and NF kappa B pathways. 942 75

We report here on stable prepackaging cell lines which can be converted into packaging cell lines for high-titer vesicular stomatitis virus G protein (VSV-G)-pseudotyped retrovirus vectors by the introduction of Cre recombinase-expressing adenovirus. The generated prepackaging cell lines constitutively express the gag-pol genes and contain an inducible transcriptional unit for the VSV-G gene. From this unit, the introduced Cre recombinase excised both a neomycin resistance (Neo(r)) gene and a poly(A) signal flanked by a tandem pair of loxP sequences and induced transcription of the VSV-G gene from the same promoter as had been used for Neo(r) expression. By inserting an mRNA-destabilizing signal into the 3' untranslated region of the Neo(r) gene to reduce the amount of Neo(r) transcript, we were able efficiently to select the clones capable of inducing VSV-G at high levels. Without the introduction of Cre recombinase, these cell lines produce neither VSV-G nor any detectable infectious virus at all, even after the transduction of a murine leukemia virus-based retrovirus vector encoding beta-galactosidase. They reproducibly produced high-titer virus stocks of VSV-G-pseudotyped retrovirus (1.0 x 10(6) infectious units/ml) from 3 days after the introduction of Cre recombinase. We also present evidence that VSV-G-producing cells are still fully susceptible to transduction by VSV-G pseudotypes. However, in this vector-producing system, which regulates VSV-G pseudotype production in an all-or-none manner, the integration of vector DNA into packaging cell lines would be minimized. We further show that heparin significantly inhibits retransduction of VSV-G pseudotypes in the culture fluids of packaging cell lines, leading to a two- to fourfold increase in the yield of the pseudotypes after induction. This vector-producing system was very stable and should be advantageous in human gene therapy.
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PMID:A new system for stringent, high-titer vesicular stomatitis virus G protein-pseudotyped retrovirus vector induction by introduction of Cre recombinase into stable prepackaging cell lines. 944 7

A novel retroviral vector has been designed based on a Friend-murine leukemia virus (Fr-MuLV) FB29 strain. The latter has been selected according to characteristics of pathogenicity in mice where it induces a disease of the haemopoietic system affecting all lineages. Higher infectivity has also been demonstrated as compared to other strains. In accordance with these findings, the amphotropic producer clone used in this study carrying along the neomycine resistance gene (FOCH-Neo), harbors viral titers over 10(7) cfu/ml. To investigate the potential of genetically engineering hematopoietic precursors, CD34+ progenitors were selected from cord blood, bone marrow, and peripheral blood mobilized stem cells (patients + solid tumors) and transduced with FOCH-Neo. High transduction rates were achieved using virus supernatant and minimal doses of hematopoietic growth factors during pretransduction and transduction steps. A polymerase chain reaction (PCR) assay investigating the presence of both neomycin-encoding and viral vector sequences tested positive in 45-90% of granulocyte-macrophage colony-forming units (CFU-GM) generating cells (bone marrow and peripheral blood derived cells) following transduction. An average of 35% colonies showed resistance to G418. Such levels of transduction proved reproducible using only supernatants harboring over 10(7) cfu/ml. In those experiments where long-term in vitro cultures could be maintained over 5 weeks (all cord blood and 5 among 23 PBSC), efficient transduction of long-term culture initiating cell (LTC-IC) hematopoietic progenitors was demonstrated on the basis of both resistance to G418 and virus integration. In the latter case, the PCR assay tested positive in as much as 35-60% of late unselected CFU-colonies. This novel retroviral vector harbors interesting features toward genetic modification of hematopoietic progenitors.
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PMID:Efficient transduction of hemopoietic CD34+ progenitors of human origin using an original retroviral vector derived from Fr-MuLV-FB29: in vitro assessment. 947 80

This report describes the results of experiments to determine whether chimeras between a retrovirus and portions of Ty3 are active in vivo. A chimera between Ty3 and a Neo(r)-marked Moloney murine leukemia virus (M-MuLV) was constructed. The C-terminal domain of M-MuLV integrase (IN) was replaced with the C-terminal domain of Ty3 IN. The chimeric retroviruses were expressed from an amphotrophic envelope packaging cell line. The virus generated was used to infect the human fibrosarcoma cell line HT1080, and cells in which integration had occurred were selected by G418 resistance. Three independently integrated viruses were rescued. In each case, the C-terminal Ty3 IN sequences were maintained and short direct repeats of the genomic DNA flanked the integration site. Sequence analysis of the genomic DNA flanking the insertion did not identify a tRNA gene; therefore, these integration events did not have Ty3 position specificity. This study showed that IN sequences from the yeast retrovirus-like element Ty3 can substitute for M-MuLV IN sequences in the C-terminal domain and contribute to IN function in vivo. It is also one of the first in vivo demonstrations of activity of a retrovirus encoding an integrase chimera. Studies of chimeras between IN species with distinctive integration patterns should complement previous work by expanding our understanding of the roles of nonconserved domains.
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PMID:A chimeric Ty3/Moloney murine leukemia virus integrase protein is active in vivo. 955 20

The effects of the protein kinase C (PKC) activator and down-regulator bryostatin 1 were examined with respect to paclitaxel-induced apoptosis and antiproliferative activity in human myeloid leukemia cells (U937) displaying enforced expression of the anti-apoptotic protein Bcl-xL. Overexpression of Bcl-xL blocked various aspects of paclitaxel-mediated apoptosis, including caspase-3 activation, degradation of poly(ADP-ribose) polymerase (PARP), loss of mitochondrial membrane potential (Delta Psim), and release of cytochrome c. However, subsequent (but not prior) exposure of paclitaxel-treated U937/Bcl-xL cells (500 nM; 6 h) to bryostatin 1 (10 nM; 15 h) restored the extent of apoptosis, caspase activation, and mitochondrial damage to levels approximating those in paclitaxel-treated empty-vector control cells (U937/Neo). Potentiation of paclitaxel-induced apoptosis by bryostatin 1 in U937/Bcl-xL cells occurred primarily in the G2M cell population, and was associated with alterations in Bcl-xL gel mobility and a reduction in paclitaxel-mediated stimulation of CDK1 activity. Enhancement of paclitaxel-induced apoptosis by bryostatin 1 in Bcl-xL overexpressors was accompanied by a corresponding reduction in clonogenic potential. In contrast to its effects on apoptosis, bryostatin 1 failed to restore paclitaxel-mediated increases in free Bax levels in U937/Bcl-xL cells. Lastly, the actions of bryostatin 1 were mimicked by a pharmacologic inhibitor of the MEK1/MAP kinase pathway (PD98059), but not by SB203580, an inhibitor of p 38 MAP kinase. Moreover, sequential exposure of both U937/Neo or/Bcl-xL cells to paclitaxel followed by bryostatin 1 or PD98059 was associated with a net reduction in MAP kinase activity. Collectively, these findings indicate that protection against paclitaxel-mediated mitochondrial dysfunction and apoptosis in human U937 leukemia cells conferred by Bcl-xL overexpression can be substantially overcome by bryostatin 1 and possibly other agents that interrupt the MAP kinase signal transduction pathway.
Leukemia 1999 Oct
PMID:Bryostatin 1 enhances paclitaxel-induced mitochondrial dysfunction and apoptosis in human leukemia cells (U937) ectopically expressing Bcl-xL. 1051 58

Recent experiments suggest an interconnection between cell proliferation and programmed cell death (apoptosis), although the detailed molecular mechanisms remain unclear. We have hypothesized that expression of some apoptosis regulators is cell cycle-dependent, which in turn influences tumor cell chemosensitivity in a cell cycle-dependent fashion. To test these hypotheses, we synchronized human leukemia Jurkat T, Neo (using aphidicolin), breast cancer MCF-7, normal fibroblast, and simian virus 40-transformed cells (by aphidicolin or serum starvation), and measured levels of several Bcl-2 family proteins. The highest expression of Bcl-2 protein was found in the G(1) phase of all the five cell lines tested. In contrast, levels of Bax protein remained relatively unchanged in four of the cell lines, and levels of Bcl-X(L), Bcl-X(S), and Bak proteins showed little or no cell cycle-dependent changes in Jurkat T cells. Similar to the changes in Bcl-2 protein levels, its mRNA expression was also G(1) phase-specific, whereas the level of a Bcl-2 cleavage activity remained constitutive. When treated with an anticancer drug (etoposide or cisplatin) or the kinase inhibitor staurosporin, the cells containing a high G(1) population and a high Bcl-2 protein level were much more resistant to the induced apoptosis than the cells containing a high S phase population and a low Bcl-2 protein level. Constitutive overexpression of Bcl-2 protein in Jurkat T cells completely blocked the S phase-associated sensitivity to these apoptosis stimuli. The cell cycle-dependent Bcl-2 protein expression seems to contribute to the regulation of chemosensitivity and apoptotic commitment of human tumor cells.
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PMID:G(1) phase-dependent expression of bcl-2 mRNA and protein correlates with chemoresistance of human cancer cells. 1104 47

Activated phosphoinositide 3-kinase (PI3K) and its downstream target Akt are essential for the fibroblast transformation induced by many viral products. Tax, encoded by human T-cell leukemia virus type I (HTLV-I), has been demonstrated to induce the transformation of rat fibroblast Rat-1 cell through NF-kappaB activation. By stable transfection of Rat-1 cells with expressing constructs of Tax and its mutant M47, which is defective in HTLV-I LTR transactivation, we selected their transformed clones, which have characteristics of NF-kappaB activation and colony formation beyond the cell monolayer (a malignant phenotype). However, these two characteristics in the transformed clones of Tax and M47 disappear after these cells have been treated with wortmannin, a specific inhibitor of PI3K. Further, increased activity of the PI3K/Akt is observed in the transformed clones of Tax and M47 as compared to the clones of empty vector Neo and the M148, which is defective in NF-kappaB activation and cell transformation. Increased activity of PI5K is present in the transformed clones of both Tax and M47 and in the M148 clone as compared to that in the Neo cell. It is known that the efficiency of Tax-induced cell transformation is not high; a minority of Tax-expressing clones show transformation, although the majority of Tax-expressing clones show activated NF-kappaB. A Tax-expressing, nontransformed clone after transfection with an active form of the catalytic subunit of PI3K, p110alpha, becomes transformed. Consistent with these results, a Tax highly-expressing human T-cell line MT2 exhibits both higher polyphosphoinositide turnover and higher activities of PI3K and PI5K than those of Jurkat or MT1 and HTLV-I-negative and a Tax-unexpressing cell line, respectively. These results demonstrate that the activation of the PI3K/Akt signaling pathway, excepting for the NF-kappaB, is also required for the cell transformation induced by Tax.
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PMID:Phosphoinositide-3 kinase-PKB/Akt pathway activation is involved in fibroblast Rat-1 transformation by human T-cell leukemia virus type I tax. 1142 Jun 61


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