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)

Recently the high transfection potential of the cationic polymer polyethylenimine (PEI) was described (Boussif O et al. Proc Natl Acad Sci USA 1995; 92: 7297-7301). To combine the promising DNA delivering activity of PEI with the concept of receptor-mediated gene delivery, cell-binding ligands (transferrin or antiCD3 antibody) were incorporated by covalent linkage to PEI. DNA complexes of PEI or ligand-PEI conjugates were tested for transfection of cultured neuroblastoma Neuro 2A cells, melanoma B16 or H225 cells, erythroid leukemic K562 cells and T cell leukemia Jurkat E6.1 cells. Depending on the cell line, incorporation of the cell-binding ligand resulted in an up to 1000-fold increased transfection efficiency. This activity depends on ligand-receptor interaction and was observed also at low PEI cation:DNA anion ratios where ligand-free PEI lacks efficiency. Depending on the cell-binding ligand, specific targeting (CD3 antibody, Jurkat cells) can be achieved. Gene transfer can be augmented by the addition of an endosome-destabilizing influenza peptide, but is not dependent on the presence of additional endosomolytic agents. Application of transferrin-PEI for the production of murine interleukin-2 in B16 cells resulted in exceptionally high secretion rates of 19 micrograms IL-2 protein per 10(6) cells per 24 h.
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PMID:Coupling of cell-binding ligands to polyethylenimine for targeted gene delivery. 927 17

Steroid esters of cynnamic acid derivatives have been synthesized by a heterogeneous Wittig reaction under sonochemical conditions from the corresponding triphenylphosphonium bromides and unprotected phenolic aldehyds using K2CO3 as a base. 5 beta-Cholan-3 alpha, 7 alpha, 12 alpha, 24-E-ferulate (11') exhibited a marked inhibitory effect on influenza virus A. The synthetic 3 alpha, 24-E-diferulates of 5 beta-cholan-3 alpha, 24- diol, 5 beta-cholan-3 alpha, 12 alpha, 24-triol and 5 beta-cholan-3 alpha, 7 alpha, 12 alpha, 24-tetrol (8, 9 and 12) showed antitumor activity on leukemia P-388 in mice.
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PMID:Transformation of cholanic acid derivatives into pharmacologically active esters of phenolic acids by heterogeneous Wittig reaction. 930 80

The fluorescence-activated cell sorter (FACS) was utilized to phenotype lymphocyte compartments in children receiving intensive chemotherapy for acute lymphoblastic leukemia (ALL). Sixteen patients (eight males and eight females) of diverse ages, risks of relapse, and within weeks 7-53 of maintenance/continuation chemotherapy treatment were arbitrarily selected for study. All 16 patients had profound B cell lymphopenia. In contrast, T cell numbers were often normal or marginally low, and accounted for up to 98% of the lymphocyte populations. No abnormality in T cell phenotypes could be demonstrated. Due to the highly skewed B/T lymphocyte ratios in these ALL patients, the absolute white blood cell counts and lymphocyte percentages were not predictive of the underlying B cell lymphopenia. Patients were also tested for serum immunoglobulin levels and most had abnormally low IgG and IgM. None of four patients immunized with the 1996-1997 influenza virus vaccine seroconverted to at least two vaccine antigens as compared to 10 of 10 healthy, age-matched controls. In total, these data highlight for the first time the profound abnormality of the B/T lymphocyte ratio in patients during treatment for ALL, and argue for consideration of B cell-targeted immunotherapy.
Leukemia 1998 Apr
PMID:Profound abnormality of the B/T lymphocyte ratio during chemotherapy for pediatric acute lymphoblastic leukemia. 955 22

Chromosomal abnormalities of band 8p11 are associated with a distinct subtype of acute myeloid leukemia with French-American-British M4/5 morphology and prominent erythrophagocytosis by the blast cells. This subtype is usually associated with the t(8;16)(p11;p13), a translocation that has recently been shown to result in a fusion between the MOZ and CBP genes. We have cloned the inv(8)(p11q13), an abnormality associated with the same leukemia phenotype, and found a novel fusion between MOZ and the nuclear receptor transcriptional coactivator TIF2/GRIP-1/NCoA-2. This gene has not previously been implicated in the pathogenesis of leukemia or other malignancies. MOZ-TIF2 retains the histone acetyltransferase homology domains of both proteins and also the CBP binding domain of TIF2. We speculate that the apparently identical leukemia cell phenotype observed in cases with the t(8;16) and the inv(8) arises by recruitment of CBP by MOZ-TIF2, resulting in modulation of the transcriptional activity of target genes by a mechanism involving abnormal histone acetylation.
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PMID:A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. 955 66

The importance and significance of amantadine- or rimantadine-resistant influenza viruses in immunocompromised patients was studied in a population of adult bone marrow transplant (BMT) recipients and patients with leukemia prospectively cultured for respiratory viruses. Influenza A viruses were isolated from 29 patients with acute respiratory illness (14 BMT recipients and 15 patients with leukemia). Fifteen patients (52%) received amantadine (n = 4) or rimantadine (n = 11) therapy. All influenza isolates recovered from six patients shedding virus for > or = 3 days were screened for antiviral susceptibility; resistant isolates were further genetically characterized. Initial influenza isolates were susceptible to amantadine or rimantadine, but subsequent isolates from five of six patients were resistant. Influenza-associated mortality was similar among patients with and without documented antiviral resistance (2 of 5 vs. 5 of 24). We conclude that development of antiviral resistance in immunocompromised individuals should be considered when they have been treated with antivirals and have shed influenza virus for a prolonged period. Isolation procedures should be instituted for all immunocompromised patients with influenza, both during and after therapy with amantadine or rimantadine.
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PMID:Common emergence of amantadine- and rimantadine-resistant influenza A viruses in symptomatic immunocompromised adults. 963 73

We report on long-term therapeutic efficacy and toxicity of recombinant interferon-alpha 2a (rIFN-alpha) in a series of 38 patients with polycythaemia vera (PV). In all patients haematocrit was first brought into the normal range by venesection; rIFN-alpha was then begun at a starting weekly dose of 9,000,000 IU. Complete response (CR) was defined as persistence of normal haematocrit without venesection and partial response (PR) as >50% reduction of phlebotomy requirement. Eleven patients (28.9%) achieved CR and 8 (21.0%) PR. Median duration of treatment for all responsive patients was 40 months; 12 patients are still responsive and under treatment after 13, 15, 25, 35, 40, 41, 43, 49, 50, 51, 52 and 52 months of therapy with rIFN-alpha. In responsive patients, rIFN-alpha also normalized leucocyte counts, platelet counts and spleen enlargement; rIFN-alpha also relieved generalized pruritus in all 10 patients displaying this symptom. Early toxicity (flu-like syndrome) was observed in 23.6% and late toxicity (severe weakness) in 13.1% of patients, requiring rIFN-alpha treatment suspension in all cases. Progression to leukaemia was observed in none of the 10 patients treated only with rIFN-alpha and in one of the 12 who received alkylating agents before enrolment in this study. According to these data, rIFN-alpha seems to be an effective and safe treatment option for PV.
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PMID:Long-term therapeutic efficacy and toxicity of recombinant interferon-alpha 2a in polycythaemia vera. 965 55

Human HLA B27-restricted cytotoxic T lymphocytes (CTL) specific for the influenza A epitope NP383-391 use similar TCR alpha and beta chains, with two closely related J alpha segments used by six of nine CTL clones from three unrelated donors (Bowness et al., Eur J. Immunol. 1993. 23: 1417-1421). The role of TCR complementarity-determining region (CDR)3alpha residues 93 and 100-102 was examined by site-directed mutagenesis, following expression of the TCR alpha and beta extracellular domains from one clone as a TCR zeta fusion heterodimer in rat basophil leukemia (RBL) cells. For the first time we have measured direct binding of tetrameric HLA B*2705/NP383-391 complexes to transfected TCR. Independently peptide-pulsed antigen-presenting cells (APC) were used to induce TCR-mediated degranulation of RBL transfectants. Our results show a key role for the conserved TCRalpha CDR3 J alpha-encoded residue Y102 in recognition of HLA B27/NP383-391. Thus the Y102D mutation abolished both tetramer binding and degranulation in the presence of peptide-pulsed APC. Even the Y102F mutation, differing only by a single hydroxyl group from the native TCR, abolished detectable degranulation. Further mutations F93A and S100R also abolished recognition. Interestingly, the N101A mutation recognized HLA B27/NP in functional assays despite having significantly reduced tetramer binding, a finding consistent with "kinetic editing" models of T cell activation. Modeling of the GRb TCR CDR3alpha loop suggests that residue Y102 contacts the HLA B*2705 alpha1 helix. It is thus possible that selection of germ-line TCRAJ-encoded residues at position 102 may be MHC driven.
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PMID:Importance of a conserved TCR J alpha-encoded tyrosine for T cell recognition of an HLA B27/peptide complex. 975 58

Plasmid DNA encoding gene products of viruses or other pathogens has recently been applied by intramuscular injection as a novel type of vaccine. It can induce cytotoxic T cell response in small animals and protect against challenge with influenza A viruses. Combinations with cytokines or DNA-encoding cytokines have been applied in order to increase the efficiency of protection. A DNA vaccine has been analyzed here against malignant melanoma encoding gp100/pmel17, a melanoma-associated antigen. A small animal model was used by injection of B16 melanoma cells to syngeneic C57Bl/6 mice. DNA vaccination before tumor cell challenge leads to about 50% reduction of tumor size. The cytokine gene coding for GM-CSF did not increase the efficiency but also led to tumor size reduction when applied alone.
Leukemia 1999 Apr
PMID:Reduced melanoma tumor formation in mice immunized with DNA expressing the melanoma-specific antigen gp100/pmel17. 1023 65

Cationic liposomes complexed with DNA have been used extensively as non-viral vectors for the intracellular delivery of reporter or therapeutic genes in culture and in vivo. However, the relationship between the features of the lipid-DNA complexes ('lipoplexes') and their mode of interaction with cells, the efficiency of gene transfer and gene expression remain to be clarified. To gain insights into these aspects, the size and zeta potential of cationic liposomes (composed of 1,2-dioleoyl-3- (trimethylammonium) propane (DOTAP) and its mixture with phosphatidylethanolamine (PE)), and their complexes with DNA at different (+/-) charge ratios were determined. A lipid mixing assay was used to assess the interaction of liposomes and lipoplexes with monocytic leukaemia cells. The use of inhibitors of endocytosis indicated that fusion of the cationic liposomes with cells occurred mainly at the plasma membrane level. However, very limited transfection of these cells was achieved using the above complexes. It is possible that the topology of the cationic liposome-DNA complexes does not allow the entry of DNA into cells through a fusion process at the plasma membrane. In an attempt to enhance transfection mediated by lipoplexes composed of DOTAP and its equimolar mixture with dioleoylphosphatidylethanolamine (DOPE) two different strategies were explored: (i) association of a targeting ligand (transferrin) to the complexes to promote their internalization, presumably by receptor-mediated endocytosis; and (ii) association of synthetic fusogenic peptides (GALA or the influenza haemagglutinin N-terminal peptide HA-2) to the complexes to promote endosomal destabilization and release of the genetic material into the cytoplasm. These strategies were effective in enhancing transfection in a large variety of cells, including epithelial and lymphoid cell lines, as well as human macrophages, especially with the use of optimized lipid/DNA (+/-) charge ratios. Besides leading to high levels of transfection, the ternary complexes of cationic liposomes, DNA, and protein or peptide, have the advantages of being active in the presence of serum and being non-toxic. Moreover, such ternary complexes present a net negative charge and, thus, are likely to alleviate the problems associated with the use of highly positively charged complexes in vivo, such as avid complexation with serum proteins. Overall, the results indicate that these complexes, and their future derivatives, may constitute viable alternatives to viral vectors for gene delivery in vivo.
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PMID:Gene delivery mediated by cationic liposomes: from biophysical aspects to enhancement of transfection. 1033 44

We have previously shown that retroviral vector particles derived from Moloney murine leukemia virus (Mo-MuLV) can efficiently incorporate influenza hemagglutinin (HA) glycoproteins from fowl plague virus (FPV), thus conferring a broad tropism to the vectors. To modify its host range, we have engineered the FPV HA to display four different polypeptides on its N terminus: the epidermal growth factor, an anti-human MHC class I molecules scFv (single-chain antibody), an anti-melanoma antigen scFv, and an IgG Fc-binding polypeptide. All recombinant HA glycoproteins were correctly expressed and processed, and efficiently incorporated into Mo-MuLV retroviral particles, indicating that amino-terminal insertion of large polypeptides did not alter the conformation of HA chimeras. Virions carrying the different chimeras bound specifically to cells expressing the targeted cell surface molecules of each ligand. In addition, all virion types were infectious but exhibited various degrees of specificity regarding the use of the targeted cell surface molecule versus the wild-type FPV HA receptor for cell entry and infection. For some ligands tested, infectivity was significantly increased on cells that express the targeted receptor, compared with cells that express only the wild-type HA receptor. Furthermore, some polypeptides could abolish infectivity via the wild-type FPV HA receptor. Our data therefore indicate that it is possible to engineer the HA envelope glycoprotein by fusing ligands to its amino-terminal end without affecting its fusion activity.
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PMID:Retroviral display of functional binding domains fused to the amino terminus of influenza hemagglutinin. 1039 78


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