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)

Community respiratory viruses, such as respiratory syncytial virus (RSV), influenza viruses, parainfluenza viruses, adenoviruses, and picornaviruses, are an important cause of respiratory disease in the immunocompromised adult with cancer. Recent studies have demonstrated that a minimum of 31% of adult bone marrow transplant (BMT) recipients and 18% of adults with leukemia who are hospitalized with an acute respiratory illness have a community respiratory virus infection. The temporal occurrence of these infections in immunocompromised patients tends to mirror their occurrence in the community. The clinical illnesses range from self-limited upper respiratory illnesses to fatal pneumonias, depending on the type of virus and the type and degree of immunosuppression. The pneumonias may be viral, bacterial/fungal, or mixed. The highest frequency of progression to fatal viral pneumonia has been reported for RSV infections in recently transplanted BMT recipients and myelosuppressed patients with leukemia. Studies have suggested that early therapy for RSV pneumonia with a combination of aerosolized ribavirin and intravenous immunoglobulin may be of benefit. Defining effective prophylactic and therapeutic strategies will be a challenge, given the diversity of viruses, the wide spectrum of immunocompromised patients with varying vulnerability to serious community respiratory virus disease, and the frequent presence of other opportunistic infections and medical problems. A combination of antiviral drugs and immunotherapy may need to be considered for their potential additive effect as well as to prevent the emergence of resistant virus, as occurs during monotherapy for influenza with amantadine or rimantadine. The optimal therapies need to be defined in controlled trials; however, it appears that a favorable response will hinge on the initiation of therapy at an early stage of the respiratory illness.
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PMID:Community respiratory virus infections in immunocompromised patients with cancer. 1086 37

To investigate the modifications of antitumor activity and DNA binding mode of transplatin after replacement of one nonleaving group NH(3) by an iminoether group, trans-[PtCl(2)(Z-HN=C(OMe)Me)(NH(3)] and trans-[PtCl(2)(E-HN=C(OMe)Me)(NH(3)] complexes (differing in the Z or E configuration of iminoether, and abbreviated mixed Z and mixed E, respectively), have been synthesized. In a panel of human tumor cell lines, both mixed Z and mixed E show a cytotoxic potency higher than that of transplatin, the mean IC(50) values being 103, 37, and 215 microM, respectively. In vivo mixed Z is more active and less toxic than mixed E in murine P388 leukemia and retains its efficacy against SK-OV-3 human cancer cell xenograft in nude mice. In the reaction with naked DNA, mixed Z forms monofunctional adducts that do not evolve into intrastrand cross-links but close slowly into interstrand cross-links between complementary guanine and cytosine residues. The monofunctional mixed Z adducts are removed by thiourea and glutathione. The interstrand cross-links behave as hinge joints, increasing the flexibility of DNA double helix. The mixed Z, transplatin, and cisplatin interstrand cross-links, as well as mixed Z monofunctional adducts are not specifically recognized by HMG1 protein, which was confirmed to be able to specifically recognize cisplatin d(GpG) intrastrand cross-links. These data demonstrate that the DNA interaction properties of the antitumor-active mixed Z are very similar to those of transplatin, thus suggesting that clinical inactivity of transplatin could not depend upon its peculiar DNA binding mode.
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PMID:Replacement of an NH(3) by an iminoether in transplatin makes an antitumor drug from an inactive compound. 1109 93

We describe a two-stage preparation of chemically engineered Ab constructs, employing as modules Fab'gamma from mAb or rAb, and Fc from human normal IgG1. A multivalent, optionally multispecific F(ab')(n) core is formed in stage one, and one or more Fc modules added in stage two. Examples include bispecific Fab(2)Fc(2) (for simplicity, primes and Greek letters are omitted from names of final constructs) and trivalent Fab(3)Fc(2), which are designed to kill neoplastic cells. An essential element in the construction is the availability of the Fab' in two reduced forms, Fab'(-sulfhydryl (SH))(5) and Fab'-SH. The first is obtained by full reduction of the interchain disulfide bonds (SS) in the F(ab')(2) fragment of IgG. Fab'-SH is obtained by disulfide-interchange reactions on Fab'(-SH)(5), whereby the gamma-light SS is reconstituted, an unusual intrachain SS forms in the gamma-chain hinge, and one hinge SH remains. F(ab')(2) and F(ab')(3) cores are built using partially reduced modules, being given intermodular thioether links that resist reduction. These cores are then fully reduced, making available SH groups for addition of the Fcgamma modules. In the final constructs, all intermodular links embody tandem thioether bonds arising at hinge-region cysteines. Cytotoxic activities of representative constructs, and some enhancements deriving from multiple modules, are assessed. In guinea pigs, catabolism of Fab(2)Fc(2) yielded a t(1/2) similar to that of human IgG1, although the serum Fab(2)Fc(2) revealed some proteolytic breakdown not shown by the IgG1. Immunotherapy of a guinea-pig leukemia confirmed the ability of these constructs to kill target cells in vivo.
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PMID:Thioether-bonded constructs of Fab'gamma and Fc gamma modules utilizing differential reduction of interchain disulfide bonds. 1114 16

The function of the N terminus of the murine leukemia virus (MuLV) surface (SU) protein was examined. A series of five chimeric envelope proteins (Env) were generated in which the N terminus of amphotropic 4070A was replaced by equivalent sequences from ecotropic Moloney MuLV (M-MuLV). Viral titers of these chimeras indicate that exchange with homologous sequences could be tolerated, up to V17eco/T15ampho (crossover III). Constructs encoding the first 28 amino acids (aa) of ecotropic M-MuLV resulted in Env expression and binding to the receptor; however, the virus titer was reduced 5- to 45-fold, indicating a postbinding block. Additional exchange beyond the first 28 aa of ecotropic MuLV Env resulted in defective protein expression. These N-terminal chimeras were also introduced into the AE4 chimeric Env backbone containing the amphotropic receptor binding domain joined at the hinge region to the ecotropic SU C terminus. In this backbone, introduction of the first 17 aa of the ecotropic Env protein significantly increased the titer compared to that of its parental chimera AE4, implying a functional coordination between the N terminus of SU and the C terminus of the SU and/or transmembrane proteins. These data functionally dissect the N-terminal sequence of the MuLV Env protein and identify differential effects on receptor-mediated entry.
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PMID:Functional characterization of the N termini of murine leukemia virus envelope proteins. 1128 84

We describe herein a case of nephrotic syndrome (NS) following allogeneic bone marrow transplantation (allo-BMT) for natural killer cell leukemia/lymphoma. Histologic studies defined the diagnosis as crescentic glomerulonephritis with massive immunoglobulin A (IgA) deposition, which has never been reported in NS cases following allo-BMT. Most of the massive infiltrated cells in the interstice were CD3(+)CD4(-)CD8(+) T cells derived from the donor. We observed mesangial deposition of Haemophilus parainfluenza outer membrane (OMHP) antigen and decreased glycosylation of the IgA1 hinge in the recipient's samples is consistent with the recently reported pathogenesis of IgA nephropathy. Further, the titer of IgA antibody against the donor serum was as high as other IgA nephropathy cases. These findings suggest that NS and crescentic glomerulonephritis in this case occurred as one of the forms of chronic graft-versus-host disease (GVHD), and that IgA deposition was associated with H parainfluenza and decreased glycosylation of the IgA1 hinge.
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PMID:Nephrotic syndrome with crescent formation and massive IgA deposition following allogeneic bone marrow transplantation for natural killer cell leukemia/lymphoma. 1254 67

Many gene therapy approaches require specific, efficient gene delivery to cells in vivo. To target colorectal tumors we fused a single-chain variable fragment (scFv) directed against carcinoembryonic antigen (CEA) to the amphotropic murine leukemia virus envelope. A proline-rich hinge and matrix metalloprotease (MMP) cleavage site linked the two proteins. Following attachment to CEA, MMP cleavage of the envelope at the cell surface removed the scFv and proline-rich hinge, allowing transduction. This allowed selective targeting of CEA-positive cells in vivo after injection of producer cells at the site of the tumor, with up to 10% of cells within a CEA-positive tumor xenograft becoming transduced. Intraperitoneal injection of amphotropic producer cells resulted in transduction of cells in spleen, liver, and kidney, which was not detected when CEA-targeted producer cells were used. These results demonstrate the feasibility of using targeted retroviral vectors for in vivo gene delivery to tumors. Furthermore, the lack of transduction of host cells eliminates the risk of insertional mutagenesis leading to transformation of host hematopoietic cells.
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PMID:Efficient retroviral vector targeting of carcinoembryonic antigen-positive tumors. 1474 81

To develop a therapy for drug-resistant B-lineage acute lymphoblastic leukemia (ALL), we transduced T lymphocytes with anti-CD19 chimeric receptors, consisting of an anti-CD19 single-chain variable domain (reactive with most ALL cases), the hinge and transmembrane domains of CD8alpha, and the signaling domain of CD3zeta. We compared the antileukemic activity mediated by a novel receptor ('anti-CD19-BB-zeta') containing the signaling domain of 4-1BB (CD137; a crucial molecule for T-cell antitumor activity) to that of a receptor lacking costimulatory molecules. Retroviral transduction produced efficient and durable receptor expression in human T cells. Lymphocytes expressing anti-CD19-BB-zeta receptors exerted powerful and specific cytotoxicity against ALL cells, which was superior to that of lymphocytes with receptors lacking 4-1BB. Anti-CD19-BB-zeta lymphocytes were remarkably effective in cocultures with bone marrow mesenchymal cells, and against leukemic cells from patients with drug-resistant ALL: as few as 1% anti-CD19-BB-zeta-transduced T cells eliminated most ALL cells within 5 days. These cells also expanded and produced interleukin-2 in response to ALL cells at much higher rates than those of lymphocytes expressing equivalent receptors lacking 4-1BB. We conclude that anti-CD19 chimeric receptors containing 4-1BB are a powerful new tool for T-cell therapy of B-lineage ALL and other CD19+ B-lymphoid malignancies.
Leukemia 2004 Apr
PMID:Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. 1496 Oct 35

Pim-1 is an oncogene-encoded serine/threonine kinase primarily expressed in hematopoietic and germ cell lines. Pim-1 kinase was originally identified in Maloney murine leukemia virus-induced T-cell lymphomas and is associated with multiple cellular functions such as proliferation, survival, differentiation, apoptosis, and tumorigenesis (Wang, Z., Bhattacharya, N., Weaver, M., Petersen, K., Meyer, M., Gapter, L., and Magnuson, N. S. (2001) J. Vet. Sci. 2, 167-179). The crystal structures of Pim-1 complexed with staurosporine and adenosine were determined. Although a typical two-domain serine/threonine protein kinase fold is observed, the inter-domain hinge region is unusual in both sequence and conformation; a two-residue insertion causes the hinge to bulge away from the ATP-binding pocket, and a proline residue in the hinge removes a conserved main chain hydrogen bond donor. Without this hydrogen bond, van der Waals interactions with the hinge serve to position the ligand. The hinge region of Pim-1 resembles that of phosphatidylinositol 3-kinase more closely than it does other protein kinases. Although the phosphatidylinositol 3-kinase inhibitor LY294002 also inhibits Pim-1, the structure of the LY294002.Pim-1 complex reveals a new binding mode that may be general for Ser/Thr kinases.
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PMID:Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002. 1565 54

A novel bivalent single chain fusion protein, Bic3, was assembled consisting of the catalytic and translocation domains of diphtheria toxin (DT(390)) fused to two repeating sFv molecules recognizing human CD3 epsilon of the human T-cell receptor. Historically, problems with these constructs include low yield, toxicity, and reduced efficacy. Instead of using conventional Gly(4)Ser linkers to connect heavy/light chains, aggregation reducing linkers (ARL) were used which when combined with a new SLS-based refolding method reduced aggregation and enhanced the yield of final product. Toxicity was reduced at least 25-fold by repeating the two sFv molecules and adding a portion of the hinge-CH2-CH3 human constant regions. The resulting Bic3 was just as cytotoxic to HPB-MLT.UM T leukemia cells in vitro (IC(50)=4 pmol) as a monovalent construct made with the same DT and sFv. In vivo, Bic3 was effective in a new and aggressive therapy model in which it significantly prolonged survival of scid mice with established human T-cell leukemia (p<0.0001 compared to controls). Importantly, no toxicity measured by weight loss, enzyme function, or histology was observed at the highest dose of Bic3 tested (2000 ug/kg). Bic3 warrants investigation as a new drug for treating T-cell malignancy and other T-cell related disorders.
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PMID:Molecular modification of a recombinant, bivalent anti-human CD3 immunotoxin (Bic3) results in reduced in vivo toxicity in mice. 1566 Dec 59

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) belongs to the family of nuclear hormone receptors (NHRs) and is a ligand-activated transcription factor. There are four mRNAs, PPAR-gamma1, PPAR-gamma2, PPAR-gamma3 and PPAR-gamma4, which encode two proteins, PPAR-gamma1and PPAR-gamma2. PPAR-gamma consists of five or six structural regions (A-F) in four functional domains. The NH2-terminal A/B domain harbors a ligand-independent transcriptional activation function (AF-1), the C domain is a DNA binding domain (DBD), the D hinge region is important for co-factor docking and the complex multifunctional COOH-terminal portion (E/F) encompasses the ligand binding domain (LBD), a dimerization interface and the ligand-dependent activation domain AF-2. Some long-chain polyunsaturated fatty acids, arachidonic acid metabolites and fatty acid derived components are natural ligands of PPAR-gamma. The anti-diabetic thiazolidinedione class of drugs, certain non-steroidal anti-inflammatory drugs (NSAIDs) and some non-thiazolidinedione tyrosine are the synthetic ligands of PPAR-gamma. After activation, it forms heterodimer with the retinoid X receptor (RXR) and then binds to specific recognition sites in the target gene, the peroxisome proliferator response elements (PPREs), and regulates transcription of specific genes. PPAR-gamma has potential anti-neoplastic effects both in solid cancer and in leukemia through inhibition of cell proliferation, induction of apoptosis and terminal differentiation, as well as inhibition of angiogenesis. The ligands of PPAR-gamma may represent a promising, novel therapeutic approach for certain human malignancies.
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PMID:Peroxisome proliferator-activated receptor gamma in malignant diseases. 1638 66


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