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)

Children with cancer represent a high-risk group for protein-energy malnutrition due to side effects associated with treatment. Assessment of nutritional status at the time of diagnosis and during treatment is, therefore, essential for planning nutritional intervention. We studied the nutritional status of 25 children with leukemia [9 newly diagnosed/relapsed (D/R) leukemic patients and 16 children with leukemia in remission (REM)]. Plasma proteins (prealbumin, PA; albumin, Alb; transferrin, Tr; retinol-binding protein, RBP) and acute phase-reactant proteins (alpha 1-acid glycoprotein, AGP; C-reactive protein, CRP; ceruloplasmin, CER) were measured by radial immunodiffusion. Results show that there were no significant deficits in anthropometric measurements among leukemic children. In contrast, the mean levels of all plasma proteins, especially PA (P < 0.005), were significantly lower in the D/R group than in the REM group. All D/R children, compared to 59% of those in remission, had PA levels < 20 mg/dl. Only the D/R group had abnormal levels of RBP, Tr, and Alb. Children who were treated with prednisone had significantly higher mean levels of PA, RBP, and AGP than those who were not receiving prednisone. The mean levels of acute phase-reactant proteins in these leukemic children were comparable to those of healthy children. We conclude that mild/moderate malnutrition is common in leukemic patients at D/R and that PA seems to be the most sensitive indicator of visceral protein status.
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PMID:Nutritional status of children with leukemia. 907 29

We report that cytosine arabinoside (Ara-C), a cytosine analogue that at low doses causes phenotypical changes on human leukemia cells in vitro and in vivo, induces growth inhibition of oropharyngeal cancer KB and lung adenocarcinoma A549 cell lines. An increase in the number of epidermal growth factor and transferrin receptors (EGFR, TrfR) is induced by Ara-C on these cells. Maximal EGFR up-regulation occurs 96 h after the beginning of Ara-C exposure while maximal TrfR up-regulation is detected 24 h later. These effects occur without changes in the affinity of EGFR and TrfR for their ligands. Two classes of EGF-binding sites with a Kd of 0.055 nM and 2.3 nM respectively, and one class of transferrin-binding sites with a Kd of about 4 nM are detected on both untreated and Ara-C-treated KB cells. [3H]Thymidine uptake is clearly stimulated on KB cells by nanomolar concentrations of EGF and transferrin, whereas in Ara-C-treated cells [3H]thymidine uptake is not increased by EGF and transferrin under conditions where maximal EGFR and TrfR up-regulation occurs. The enhanced EGF and transferrin binding is paralleled by a twofold increase of in vitro targeting of Ara-C-treated KB and A549 cells with anti-EGFR 108.1 mAb and anti-TrfR OKT9 mAb. We propose that Ara-C could provide a new approach for the improvement of the therapeutic index of anti-EGFR and anti-TrfR immunoconjugates.
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PMID:Cytosine arabinoside increases the binding of 125I-labelled epidermal growth factor and 125I-transferrin and enhances the in vitro targeting of human tumour cells with anti-(growth factor receptor) mAb. 839 10

Iron chelating agents have been demonstrated to inhibit tumour cell growth. However, in vitro and in vivo results using desferrioxamine a hexadentate iron chelating agent, for anti-cancer treatment are not always in agreement. Therefore, we have studied the response of three human tumour cell lines (HL-60 promyelocytic leukaemia, MCF-7 breast cancer and HepG2 hepatoma), grown in culture medium supplemented with either human pooled (HPS) or fetal bovine serum (FBS), to desferrioxamine. Desferrioxamine, at micromolar concentrations, induced severe cytotoxicity in all tumour cell lines grown in FBS medium. When grown in HPS medium, comparable desferrioxamine cytotoxicity was observed in the millimolar range. The addition of 50% saturated human transferrin to FBS medium resulted in protection against desferrioxamine cytotoxicity. HL-60 cells were further studied for iron metabolism characteristics. HL-60 cells, grown in medium with FBS, were found to have an 8.4 fold increase in surface transferrin receptor (TfR) expression (P < 0.001) as compared with HL-60 cells grown in medium with HPS. However, iron uptake of HPS cultured HL-60 cells, after incubation with saturated human transferrin, was higher, resulting in a higher concentration of iron in HPS cultured HL-60 cells as compared with FBS cultured cells (1.72 +/- 0.02 mumol/g protein v. 1.32 +/- 0.14 mumol/g protein; P < 0.001). Using desferrioxamine it was shown that TfR expression is dependent on the biological availability of iron in the cell. Consistent with the lower iron content in FBS cultured cells, we conclude that the cytotoxicity of desferrioxamine is dependent on the ability of cells to replenish cellular iron stores from the culture medium. Cells grown in FBS medium lack this ability and are therefore more susceptible to desferrioxamine.
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PMID:The in vitro response of human tumour cells to desferrioxamine is growth medium dependent. 843 91

Transferrin-neocarzinostatin (NCS) conjugates with differing molar ratios of drug to protein were synthesized and their intracellular metabolism was investigated. The conjugate mixtures of transferrin-NCS were separated by DEAE-Sephacel column chromatography. The separated molecular species were examined with respect to binding affinity to transferrin receptor, cytotoxicity and intracellular metabolism using the human leukemia cell line, K562. Transferrin-NCS conjugate is capable of binding to transferrin receptors specifically and its reactivity became weaker as the ratio of bound NCS to transferrin was increased. Transferrin-6NCS did not bind measurably to the receptor. On the other hand, the cytotoxicity was augmented when the number of NCS molecules bound per molecule of transferrin was increased to 4NCS/transferrin, while transferrin-5NCS and transferrin-6NCS species exhibited low activity. Examination of the kinetics of metabolism by pulse chase study using 125I-labeled ligand indicated that unconjugated transferrin and transferrin-NCS conjugates were internalized in similar ways, although the degradation of internalized conjugate was more marked in the case of transferrin-4NCS than transferrin-1NCS. Thus, the molar ratio of transferrin-drug conjugate could be optimized with respect to both the binding activity to receptor and the intracellular metabolic pathway.
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PMID:Intracellular metabolism and cytotoxicity of transferrin-neocarzinostatin conjugates of differing molar ratios. 846 35

Ribonucleotide reductase is the rate limiting enzyme of deoxynucleoside triphosphate synthesis and is considered to be an excellent target of cancer chemotherapy. Trimidox, a newly synthesized compound, inhibits this enzyme and has in vitro and in vivo antitumour activity. As trimidox was able to upregulate the expression of the transferrin receptor in HL-60 human promyelocytic leukaemia cells, we have now investigated the capability of trimidox to interfere with iron metabolism. We show by photometric and polarographic methods that trimidox is able for form an iron complex. However, its cytotoxic action cannot be circumvented by addition of iron-saturated transferrin or iron-ammonium citrate, indicating that the iron complexing capacity is not responsible for the mechanism of action of this compound. When HL-60, K562 or L1210 leukaemia cells were incubated with the trimidox-iron complex itself, we could observe increases of the 50% growth inhibitory capacity of the complex in comparison with trimidox alone. We conclude that trimidox is able to form an iron complex, but in contrast to other agents, the anticancer activity cannot be contributed to this effect alone. Further studies will have to elucidate the molecular mechanism of action of this new and promising anticancer agent.
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PMID:Iron binding capacity of trimidox (3,4,5-trihydroxybenzamidoxime), a new inhibitor of the enzyme ribonucleotide reductase. 862 54

A liposomal carrier system able to interact specifically with HL60 leukaemia cells was produced using small unilamellar liposomes made of pure phospholipids chemically cross-linked to human transferrin. The conjugation of transferrin to liposomes was carried out using N-succinimidyl 3-(2-pyridyldithio)-propionate and 2-iminothiolane as activating agents for the liposomes and the protein. The reaction occurred under conditions set to covalently link on the surface of a single vesicle a limited number (one to ten) of transferrin molecules, as verified by means of electron microscopy and immunoenzymic measurements. Before conjugation, the ultrastructure of the liposomes, and the content and distribution of the amino groups within the bilayer, were determined. The reactivity of the liposomes towards amino-derivatizing or thiolating compounds was also measured. Kinetic spectroscopic measurements confirmed that the distribution of the phosphatidylethanolamine in the vesicle bilayer is asymmetrical: 22% of phosphatidylethanolamine was found exposed to the external surface of the liposomes and accessible to the cross-linker. The modified liposomes were able to interact specifically with the cells and to be internalized by active receptor-mediated endocytosis, as demonstrated by the full inhibition of internalization induced by free transferrin.
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PMID:Liposomal targeting of leukaemia HL60 cells induced by transferrin-receptor endocytosis. 896 57

The plasma concentrations of erythropoietin (Ep), soluble transferrin receptors (sTfRs), iron, total iron binding capacity (TIBC) and ferritin were monitored in five leukaemia patients undergoing autologous bone marrow stem cell transplantation (BMSCT) and in 10 lymphoma and 21 ovarian cancer patients undergoing autologous peripheral blood SCT (PBSCT); 9/21 ovarian cancer patients received recombinant human G-CSF and Ep and six recombinant human GM-CSF and Ep following SCT. All parameters were evaluated in relation to the kinetics of erythroid reconstitution as evaluated by haemoglobin (Hb) and reticulocyte levels [including the fraction of immature reticulocytes, also called highly fluorescent reticulocytes (HFR)]. Leukaemia patients undergoing BMSCT showed only a delayed (occurring at days 35-50 after SCT) and partial RBC, neutrophil and platelet recovery, whereas all patients undergoing PBSCT exhibited a rapid (occurring at days 10-15 after SCT) and sustained haemopoietic recovery. The various levels of erythroid rescue observed among these patients markedly influenced the kinetics of the different parameters investigated: (i) in leukaemia BMSCT patients sTfRs declined following SCT and remained at low levels thereafter, whereas Ep, iron. TIBC and ferritin showed a progressive and significant increase; (ii) in the different groups of patients undergoing PBSCT: (a) sTfR levels first declined following SCT and then returned to pre-therapy values at days 12-16, this response preceded erythropoietic recovery; (b) Ep, total iron, TIBC and ferritin showed an initial increase in the first days following SCT and then returned to pre-therapy values. Altogether, these observations indicate that: (i) both sTfR levels and reticulocyte counts are predictive parameters of erythropoietic recovery; (ii) coordinated changes of biochemical parameters underlying iron metabolism (iron, TIBC and ferritin) accompany erythroid rescue following SCT.
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PMID:Autologous stem cell transplantation: evaluation of erythropoietic reconstitution by highly fluorescent reticulocyte counts, erythropoietin, soluble transferrin receptors, ferritin, TIBC and iron dosages. 907 20

The level of various G1 cyclins and cyclin-dependent kinases (cdks) present in the nuclei of synchronized ML-1 human myeloblastic leukemia cells was determined as a function of time after initiation of cell growth with insulin-like growth factor-1 (IGF-1) and transferrin (Tf), and following induction of differentiation with transforming growth factor-beta1 (TGF-beta1). Cyclin E and cdk2 were expressed at relatively high levels in the nuclei of proliferation-stimulated cells, whereas cyclin D1 and cdk5 were expressed at comparably high levels in the nuclei of differentiation-induced cells. In the nuclear extracts from proliferation-stimulated cells, cyclin E complexed specifically with cdk2, whereas in nuclear extracts from differentiation-induced cells, cyclin D1 bound specifically to cdk5. Increased cyclin E/cdk2 expression was accompanied by increased DNA synthesis, whereas increased cyclin D1/cdk5 levels correlated with decreased DNA synthesis. In both growth- and differentiation-induced cells, cyclin D2 expression preceded the expression of cyclin D3, and a significantly larger amount of these cyclins was present in differentiation- as compared to proliferation-induced cells. In contrast, cdk4 and cdk6 were present at similar levels in the nuclear extracts from both growth- and differentiation-induced cells. These data show that, in ML-1 cells, the proliferation-associated progression from G1 to S, as well as the differentiation-associated transit from G1 to maturation is accompanied by the expression of specific cyclin/cdk pairs, comprising cdk2/cyclin E in growth and cdk5/cyclin D1 in differentiation.
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PMID:Differential expression of proteins regulating cell cycle progression in growth vs. differentiation. 915 Feb 73

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

A macromolecular conjugate of mitomycin C (MMC) with transferrin (TF) which possessed binding ability for TF receptor was synthesized. The conjugate (TF-MMC) was internalized into the human leukemia cell line HL60 cells and distributed into intracellular fractions, then exocytosed into an incubation medium. Although these phenomena were similar to those of TF, part of the internalized TF-MMC was degraded to a trichloroacetic acid (TCA)-soluble fraction. Therefore, the intracellular disposition of the conjugate was analyzed kinetically. The mean time of internalization of TF-MMC (7.14 min) was longer than that of TF (5.46 min). The mean exocytosis time of TF-MMC (22.1 min) was also longer than that of TF (13.0 min). Although elongation of both the internalization and exocytosis steps was responsible for the increase in recycling time of the conjugate, the binding process to the TF receptor in the internalization stage was found to be markedly retarded. The recycling times of TF-MMC and TF were 29.2 and 18.5 min, respectively. The mean decomposition time of TF-MMC was 76.3 min. Proliferation of HL60 cells was inhibited by TF-MMC in vitro. These results indicate that the TF-MMC was internalized via a TF receptor and a part of the internalized TF-MMC was degraded, so the released MMC might represent antitumor activity. TF-MMC was demonstrated to be a useful hybrid as a receptor-mediated targeting system.
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PMID:Intracellular disposition and cytotoxicity of transferrin-mitomycin C conjugate in HL60 cells as a receptor-mediated drug targeting system. 951 9


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