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)

Thalidomide is in clinical use for the treatment of graft-versus-host disease in leukemia patients after bone marrow transplant. Low levels of the drug in plasma after oral administration have made an intravenous thalidomide formulation desirable. Thalidomide, however, is sparingly soluble in aqueous solution (50 micrograms/mL) and unstable. Complexation with hydroxypropyl-beta-cyclodextrin has significantly improved the aqueous solubility and stability of thalidomide. Results obtained with HPLC and 1H NMR spectrometry have demonstrated that the solubility is increased to 1.7 mg/mL and the half-life of a diluted solution is extended from 2.1 to 4.1 h. Hence, an intravenous thalidomide-hydroxypropyl- beta-cyclodextrin solution has the potential to significantly improve current therapy for graft-versus-host disease by providing sustained high levels of drug in the plasma.
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PMID:Improvements in solubility and stability of thalidomide upon complexation with hydroxypropyl-beta-cyclodextrin. 140 4

The lineage and state of differentiation of cells in the mammalian haemopoietic compartment is associated with specific patterns of homeobox gene expression (EMBO J. 7, 2131, 1988). Agents which influence homeobox gene expression are thus of great interest in the study of human leukemias. Retinoic acid has direct regulatory actions on homeobox gene transcription (TIBS 158, 52, 1989; Differentiation 37, 773, 1988) and can induce select human leukemia cell lines to undergo terminal differentiation in vitro (Proc. natl Acad. Sci. U.S.A. 77, 2936, 1980). Retinoic acid is also a known teratogen for vertebrate foetal limb-bud development. Some of the teratogenic effects are duplicated by the drug Thalidomide (Embryopathic Activity of Drugs, Little Brown, Boston, p. 167, 1965; Haematological Cytology, Wolf Med. Pub. Ltd, London, p. 118, 1982). To investigate Thalidomide for other retinoid-like effects, we exposed cultures of human leukemia K562 cells to the metabolites generated in a Thalidomide hepatic-microsomal enzyme drug metabolizing system (Proc. natl Acad. Sci. U.S.A. 78, 2545, 1981). Here we report evidence that a single 2 h pulse-exposure to Thalidomide metabolites, induces K562 cells to undergo morphological differentiation in vitro. We also demonstrate a significant cytotoxic effect for these metabolites.
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PMID:Induction of morphological differentiation in the human leukemic cell line K562 by exposure to thalidomide metabolites. 201 4

Leukemic cell growth in the marrow microenvironment may be modulated by stromal cell products, including stimulatory growth factors and the inhibitory regulator prostaglandin E. The production of both of these stromal cell products induced by cytokine mediators appears to be closely linked. Cyclic AMP (cAMP) is an intracellular second messenger that inhibits myeloid cell proliferation and is produced in myeloid leukemia cells on stimulation of adenylate cyclase enzyme by prostaglandin E1 (PGE1). Cells expressing the product of an RAS oncogene have been observed to display diminished hormone-stimulated adenylate cyclase of membranes. If this observation were applicable to myeloid cells, a potentially important mode for leukemia cells expressing p21 RAS to escape inhibitory regulation within the hematopoietic microenvironment would be identified. We studied an interleukin-3 (IL-3)-dependent myeloid cell line, NFS/N1.H7, and a derivative line transfected with H-RAS codon 12 (T24) oncogene, H7 Neo Ras.F3, for inhibition of proliferation by PGE1, 1 microM, alone or in combination with pertussis toxin, which inactivates Gi, an inhibitory regulatory guanosine triphosphate (GTP)-binding protein of adenylate cyclase. NFS/N1.H7 cells were inhibited in interleukin-3-dependent proliferation (dose range, IL-3 10 to 100 U/mL) by PGE1 79 +/- 11%, by pertussis toxin 51 +/- 9%, and by the combination 92 +/- 2%, whereas H7 Neo RAS.F3 was inhibited 51 +/- 7%, 6 +/- 2%, or 58 +/- 9% by PGE1, pertussis toxin, and the combination, respectively. These differences in capacity for inhibition by adenylate cyclase agonists between RAS-transfectant cells (lower inhibition) versus parent cells (greater inhibition) were all highly significant (P less than .0005). Intracellular cAMP formed on PGE1 stimulation of pertussis-intoxicated cells was 150% lower in RAS-transfectant cells than in parent cells. The adenylate cyclase activity of membranes from pertussis-intoxicated RAS-transfected cells was 1.5 to two times lower than that of pertussis-intoxicated parent-cell membranes on Mg2+-dependent activation by hormone and/or guanine nucleotide. However, very similar adenylate cyclase activity was observed in oncogenic p21 RAS-containing membranes compared with parental membranes under conditions of direct activation by 4 mM Mn2+ and forskolin, where inhibitory or stimulatory G-protein influences are minimal. These studies showed diminished adenylate cyclase activity in mutant RAS-bearing myeloid-cell membranes compared with parent-cell membranes independent of the pertussis toxin-sensitive G protein, Gi.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effector function for RAS oncogene in interleukin-3-dependent myeloid cells involves diminished efficacy of prostaglandin E1-mediated inhibition of proliferation. 267 12

Retroviral-mediated gene transfer to multipotent and committed hematopoietic stem cells and marrow stromal cells was evaluated in long-term bone marrow cultures (LTBMCs). The retroviral vector pZIP-Neo(SV)(X) carrying the bacterial neomycin resistance (neor) gene that confers resistance to the neomycin analog G418 in mammalian cells was packaged in a Moloney envelope either as a replication-competent or replication-defective virus. Virus was introduced by infection of long-term marrow cultures at day 7. During a period of 12 weeks in culture, 10%-50% of harvested hematopoietic progenitor cells that formed differentiated CFU-GEMM colonies in response to pokeweed mitogen-containing spleen cell-conditioned medium (SCCM) and erythropoietin expressed the neor gene. In contrast, 1%-10% of hematopoietic progenitor cells that formed colonies in agar in response to WEHI-3B- or L-cell-conditioned medium expressed resistance to G418. The percentage of resistant progenitors was not detectably enhanced when replication-competent Moloney murine leukemia virus (M-MuLV) was present as helper virus, even though M-MuLV infected greater than 90% of cells in the long-term marrow cultures. In a separate CFU-F assay, 12%-17% of the adherent stromal cells in LTBMCs were found to express the neor gene. Thus gene transfer is limited by the fraction of progenitor cells that can integrate and express the transferred genetic sequences, rather than by the fraction of cells that are initially infected by the vector.
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PMID:Expression of a selectable gene transferred by a retroviral vector to hematopoietic stem cells and stromal cells in murine continuous bone marrow cultures. 381 49

To determine future possibilities for gene transfer, we evaluated whether myeloid progenitor cells from human umbilical cord blood (CB) could be frozen, thawed in viable form and transduced with a Neomycin resistance (NeoR) gene using retroviral vectors, and if fresh progenitor cells transduced with a Neo gene could be cryopreserved and recovered. Fresh and thawed cryopreserved nonadherent low-density T-lymphocyte depleted (NALT-) CB cells were assayed before and after gene transduction for colony formation in the presence of multiple growth factors in the absence and presence of G418. The results demonstrate that the NeoR gene could be introduced into thawed cryopreserved myeloid progenitor cells at an efficiency similar to that of fresh cells and that fresh cells transduced with the NeoR gene could be frozen in a cryopreserved state and recovered after thawing. Proviral integration, as assessed by PCR/Southern Analysis, confirmed the G418R colony data. Proviral integration was detected not only in primary G418R-colonies, but also in replated colonies in secondary dishes derived from G418R-multipotential progenitor cells (CFU-GEMM) suggesting stable integration of the transduced gene into early subsets of replatable progenitors. This information may be of use clinically.
Leukemia 1995 Oct
PMID:Cryopreserved cord blood myeloid progenitor cells can serve as targets for retroviral-mediated gene transduction and gene-transduced progenitors can be cryopreserved and recovered. 747 3

Recently, there has been renewed interest in the concept of tumor vaccines using genetically engineered tumor cells expressing a variety of cytokines to increase their immunogenicity. Human MCP-1 (JE) is a potent chemoattractant and activator of monocytes and T lymphocytes and thus a good candidate gene for a tumor vaccine. We therefore evaluated the efficacy of vaccines consisting of irradiated tumor cells transduced with the murine MCP-1 gene in the syngeneic 9L gliosarcoma brain tumor model. 9L cell lines stably expressing murine MCP-1 (9L-JE) and control cell lines expressing neomycin 3' phosphotransferase (9L-Neo) were generated by infection with a Moloney murine leukemia retroviral vector. Fisher 344 rats were immunized with intradermal injections of 5 x 10(5) or 2 x 10(6) irradiated (5000 cGy) 9L-JE, 9L-Neo, and wild-type 9L (9L-WT) cells. Two weeks later immunized and non-immunized animals were challenged with various doses of intradermal (5 x 10(6)-5 x 10(7) or intracerebral (2 x 10(4)-5 x 10(5) 9L-WT cells. Intradermal tumors grew in all non-immunized animals. No tumors grew in animals immunized with irradiated 9L-JE or 9L-Neo cells and challenged with inocula of fewer than 5 x 10(5) 9L-WT cells. With higher inocula up to 10(7) cells, tumors appeared in all the animals, but subsequently regressed in the immunized animals. Tumors in animals immunized with 9L-JE were always smaller than tumors in the other groups. In addition, only the 9L-JE vaccine protected against tumor inocula of 5 x 10(7) cells. Thus vaccination with MCP-1-expressing cells was able to protect animals against at least a 100-fold larger number of challenge tumor cells than vaccination with control cells. In contrast to studies with intradermal tumors, immunization with 9L-JE and 9L-Neo produced only minimal protection against intracerebral tumors. There was no significant difference between the 9L-JE and 9L-Neo vaccines in intracerebral challenge. This study suggests that tumor vaccines expressing cytokine genes such as MCP-1 can increase the antitumor response. However, the protective effect of these vaccines appears to be largely limited to intradermal tumors rather than intracerebral tumors.
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PMID:Monocyte chemoattractant protein-1 (MCP-1) gene transduction: an effective tumor vaccine strategy for non-intracranial tumors. 748 65

The relative efficiency of retroviral-mediated gene transfer into early-passage cultures of different tissues of fetal lamb was investigated. Monolayer cultures prepared by plating 1 x 10(6) cells were infected with the Moloney murine leukemia (MoMLV)-based vector pZIP Neo at a multiplicity of infection (moi) of approximately 1 pfu per 2 x 10(2) recipient cells prior to selection for neomycin resistance. At the low moi used, cells from different tissues showed marked differences in efficiency of colony formation in the descending order: brain > kidney > muscle, lung > skin. Brain cells were transduced at least an order of magnitude more efficiently than other cell types, despite the doubling time of brain cell cultures being five times as long. Cultures were analyzed by morphological and immunocytological criteria to determine whether any particular cell types were transduced. A wide variety of morphologically distinct neuron-like and glial-like brain cells were neomycin resistant. The majority of muscle cell colonies were myogenic. Approximately half of the large kidney colonies were epithelial-like. The majority of lung colonies consisted of fibroblasts. The results suggest that cells originating from the surface embryonic germ layer (ectoderm) and/or occupying positions near the fetal external surface have a markedly lower susceptibility to retroviral-mediated gene transduction.
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PMID:Variable efficiency of retroviral-mediated gene transfer into early-passage cultures of fetal lamb epithelial, mesenchymal, and neuroectodermal tissues. 801 44

The purpose of this study is to develop a new way for leukemia patients to tolerate an ablative chemoradiotherapy without BMT. Previous studies had demonstrated that only a few leukemia cells remained in the body during remission phase following chemotherapy and did not migrate to distant organs via the circulation until they had given rise to 3-4 x 10(5) new cells. The period required for such growth was about 20 days. However, hematopoietic stem cells migrate earlier than do leukemia cells. Therefore, alternate half body irradiation (HBI) within this period would kill the residual leukemia cells, but hematopoietic stem cells would migrate from shielded marrow to irradiated marrow and reconstruct hematopoiesis. BN rats were injected i.v. with 10 BNML subline LT12nl #15 cells, which had been transfected with the E. coli Lac-Z and Neo genes by retrovirus-mediated gene transfer. Cytochemical X-gal staining was used to identify the leukemia cells in agar culture. At day 9 after inoculation of leukemia cells, the rats were treated with cyclophosphamide (Cy 120 mg/kg), and 3 days later irradiated with 10 Gy (2 Gy/min, 6 MV, X-rays) on the upper half body, with the lower body shielded by a lead brick. They were then irradiated with the same dosage in the lower body with the upper half body shielded a week later. The preliminary results were as follow: At day 9 after inoculation, the cellularity of bone marrow (humerus, sternum, femur and tibia) was in the normal range, and the number of L-CFU ranged from 3.6 x 10(-5) to 9.0 x 10(-5) in agar culture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Experimental studies on the elimination of minimal residual leukemia in vivo by alternate half body irradiation]. 832 33

Moloney murine leukemia virus (MLV) having the gag coding region alone, G3.6, produced a low level of mRNA (1/10 of the wild-type level). Ligation of 441 nucleotides (nt) containing a splice acceptor (SA) site to the downstream portion of the remaining gag region restored the level of the unspliced message, simultaneously activating a cryptic splice donor (SD) site in the middle of the p30 coding region (between nt 1596 and 1597). Ligation of the 441 nt in the same site in the inverted orientation also increased the level of the unspliced message, activating the same SD site (between nt 1596 and 1597) and a new SA site just in front of the inserted 441 nt (between nt 4770 and 4771). Deletion or inversion of the 441-nt SA sequence from the wild-type MLV or from int in-frame deletion or int frameshift mutant MLVs of nearly full size resulted in the loss of spliced mRNA and concomitantly in a severe reduction of the unspliced mRNA, particularly at 37 degrees C. Deletion of the 5' SD site did not result in the reduction of the unspliced-mRNA level. When the gag region in G3.6 was replaced with a Neo(r) coding region, the level of expression was high. The data taken together suggest that the presence of an SA signal is necessary for high-level expression of unspliced mRNA encoding Gag or Gag-Pol.
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PMID:Possible role of splice acceptor site in expression of unspliced gag-containing message of Moloney murine leukemia virus. 864 55

Regulation by thalidomide [N(alpha)-phthalimidoglutarimide] of tumor necrosis factor (TNF)-alpha production was found to be inducer-specific. Thalidomide enhances TNF-alpha production by human leukemia HL-60 cells induced with 12-O-tetradecanoylphorbol 13-acetate (TPA), while it inhibits TNF-alpha production induced with okadaic acid (OA) in the same cell line. Some phthalimide analogs, included PP-33 [2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione] and its 4,5,6,7-tetrafluora derivative FPP-33), also showed such an inducer-specific bidirectional TNF-alpha production-regulating activity. The structure-activity relationships of the compounds tested are similar, but not identical, in the TPA-stimulated HL-60 and OA-stimulated HL-60 assay systems.
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PMID:Inducer-specific bidirectional regulation by thalidomide and phenylphthalimides of tumor necrosis factor-alpha production. 870 5


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