UMLS:C0023418 - FACTA Search

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)

The conjugates of some kinds of anticancer agents with chitin and chitosan derivatives display good anticancer effects with a decrease in the adverse effects of the original drug due to a predominant distribution into the cancer and a gradual release of free drug from the conjugates. For instance, doxifluridine and 1-beta-D-arabinofuranosylcytosine (Ara-C) were conjugated with chitosan via glutaric spacer, and the conjugates of Ara-C with chitosan, in particular, showed a good antitumour effect against P388-bearing leukemia model mice. Glycol-chitosan (G-Chi) was distributed mainly in the systemic circulation and the kidney after i.v. administration into normal mice, and retained long in the kidney. The therapeutic effect of the conjugates of mitomycin C (MMC) with G-Chi was not necessarily improved in comparison with that of the free drug, but toxic side-effects appeared to decrease with the conjugates. The conjugates of MMC with 6-O-carboxymethyl-chitin showed almost complete suppression of tumour growth at 10 mg eq. MMC/kg, though a lethal adverse effect was also observed. The conjugates of MMC with N-succinyl-chitosan showed good antitumour activities against various tumour models due to their predominant distribution into the tumour tissue and sustained-release characteristics, irrespective of water-insoluble and -soluble formulations. It is believed that the chitin and chitosan derivatives discussed in this review are good candidates for a polymeric drug carrier in cancer chemotherapy.
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PMID:Contribution of chitosan and its derivatives to cancer chemotherapy. 1579 90

The discovery of the tumour-inhibitory properties of asparaginase began 50 years ago with the observation that guinea-pig serum-treated lymphoma-bearing mice underwent rapid and often complete regression. Soon afterwards, the asparaginase of bacterial origin was isolated. The asparaginases of bacterial origin induce anti-asparaginase neutralising antibodies in a large proportion of patients (44-60%), thus negating the specific enzymatic activity and resulting in failure of the target amino acid deamination in serum. There is immunological cross-reaction between the antibodies against various formulations of native Escherichia coli-asparaginase and polyethylene glycol (PEG)-asparaginases, but not to Erwinia asparaginase, as suggested by laboratory preclinical findings. This evidence was strongly inferred from the interim analyses in the Children's Cancer Group (CCG)-1961 study. Thus, anti-E. coli or PEG-asparaginase antibodies seropositive patients may benefit from the Erwinia asparaginase. The inter-relationships between asparaginase activity, asparagine (ASN) and glutamine deamination remain largely unexplored in patients. Studies have shown that ASN depletion is insufficient to induce apoptosis in T lymphoblasts in vitro and that the inhibitory concentration of CEM T-cell line is correlated with the asparaginase concentration responsible for 50% glutamine deamination. The optimal catalysis of ASN and glutamine deamination in serum by asparaginase induces apoptosis of leukaemic lymphoblasts. The percentage of ASN and glutamine deamination was predicted by asparaginase activity. Asparaginase activity of 0.1 IU/mL provided insufficient depletion of both amino acids in high-risk acute lymphoblastic leukaemia (ALL) patients. With increasing glutamine deamination, mean asparaginase activities and percentages of post-treatment samples with effective ASN depletion (<3 micromol/L) increase. Both glutamine and ASN deamination are predicted by asparaginase activity. Further population analyses resulted in identification of sigmoid relationships between asparaginase levels and post-treatment glutamine and ASN deamination.Furthermore, pharmacodynamic analyses strongly suggested that >/=90% deamination of glutamine must occur before optimal ASN deamination takes place, due to the de novo ASN biosynthesis by the liver. These pharmacodynamic results from the best-fit population pharmacokinetic/pharmacodynamic model obtained from nonlinear mixed effects model pharmacodynamic analyses for standard-risk ALL patients are similar. These analyses produced the following results: (i) asparaginase activity </=0.4 IU/mL provided insufficient deamination of ASN, whereas >0.4-0.7 IU/mL was required for optimal (90%) ASN and glutamine deamination; and (ii) deamination of glutamine is dependent on asparaginase activity and it correlates with enhanced serum ASN deamination. Thus, glutamine deamination enhances asparaginase efficacy in ALL patients. Deamination of ASN >/=90% of control or ASN concentration <3 micromol/L may be associated with improved survival in this subset of patients. Our findings support the pharmacodynamic mechanism of PEG-asparaginase for disease control in ALL patients. These results taken together strongly support new experimental approaches for application of population pharmacokinetic/pharmacodynamic analyses to further enhance survival of leukaemia patients.
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PMID:Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future. 1582 51

Idarubicin has been successfully encapsulated in cholesterol-free liposomes, however, little is known about how the rate of drug release from circulating liposomes influences therapeutic activity. The studies described herein assess the attributes of a liposome formulation required to significantly increase the plasma levels of idarubicin and further establish whether increases in the circulation longevity of the drug mediate improved antitumor activity. Pharmacokinetic assessments of 6 different 3[H]-labelled liposome formulations were compared to free idarubicin. The highest idarubicin plasma concentrations were observed with DSPC/DSPE-PEG2000 liposomes formulated with 2 mol% DSPE-PEG2000 and 150 mM (iso-osmotic) internal citrate concentration. It was shown that increased levels of PEG-lipid incorporation augmented IDA release and the optimal liposomal formulation needed to be prepared under iso-osmotic conditions. For efficacy studies in a murine leukemia model, groups of 12-14 mice were treated i.v. with saline or equivalent doses (1, 2, 3 mg/kg) of free or liposomal IDA. Liposomal treatment groups exhibited a higher % increase in life span (ILS) as compared to equivalent doses of free drug. Efficacy studies completed in two drug resistant models, P388/ADR and MDA435LCC6/MDR1, demonstrated that neither the free nor liposomal formulation of idarubicin was therapeutically active. Encapsulation of IDA in liposomes increased antitumor activity in an IDA sensitive model, however, the significant increase in plasma drug levels was not sufficient to overcome multidrug resistance.
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PMID:Substantial increases in idarubicin plasma concentration by liposome encapsulation mediates improved antitumor activity. 1587 92

Poly(gamma-benzyl L-glutamate) (PBLG)/poly(ethylene glycol) (PEG) diblock copolymer endcapped with galactose moiety (abbreviated as GEG) was synthesized and characterized for study of liver-specific targeting. From dynamic light scattering measurement, particle sizes of copolymeric nanoparticles were decreased with an increase of PEG in the copolymer. The morphology of GEG-3 nanoparticles observed by transmission electron micrograph was observed as almost spherical shapes and ranged about 50-300 nm. From the structural characterization using 1H nuclear magnetic resonance, both characteristic peaks of PBLG and PEG were visible in CDCl3 but the characteristic peaks of PBLG were invisible in D2O, indicating that GEG block copolymers are found to the core-shell type nanoparticles in water with PBLG innercore and PEG outershell, exposing that galactose moiety of GEG block copolymers are outerwards oriented on the nanoparticle surfaces. By galactose-specific aggregation test of particles using beta-galactose specific lectin, and flow cytometry measurement, specific interaction between asialoglycoprotein receptors (ASGPR) of HepG2, human hepatoma cell line, and galactose moieties of the GEG nanoparticles was confirmed. From cell cytotoxicity test, HepG2 cells with ASGPR are more sensitive to paclitaxel (TX)-loaded nanoparticles than free TX whereas, P388 cells, murine leukemia cell line, and SK-Hep 01, human hepatoma cell line, without ASGPR is less sensitive to TX-loaded nanoparticles than free TX, suggesting that specific interaction between HepG2 cells and galactose moiety of the nanoparticles occurred.
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PMID:Cellular recognition of paclitaxel-loaded polymeric nanoparticles composed of poly(gamma-benzyl L-glutamate) and poly(ethylene glycol) diblock copolymer endcapped with galactose moiety. 1588 67

A new biodegradable water-soluble phosphazene trimer-doxorubicin conjugate was synthesized, in which equimolar hydrophilic methoxy-poly(ethylene glycol) with a molecular weight of 350 (MPEG350) and a tumor-specific tetrapeptide (Gly-Phe-Leu-Gly) were grafted to cyclotriphosphazene. The present conjugate exhibited cytotoxicity lower than that of free doxorubicin (IC50=0.10 microM) but a reasonably higher in vitro cytotoxicity (IC50=1.1 microM) against the leukemia L1210 cell line probably due to its enzymatically controlled release.
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PMID:A macromolecular prodrug of doxorubicin conjugated to a biodegradable cyclotriphosphazene bearing a tetrapeptide. 1598 76

Relapsed or refractory leukemia remains the most common therapeutic problem in pediatric oncology. Particularly challenging is the patient who has recurrence following a stem cell transplant. Insights into the molecular pathogenesis of the leukemias have produced an array of new agents. These new agents will be more selective in hitting their targets, and so their use will be more narrowly defined than with classical cytotoxic drugs. These new agents include all-trans retinoic acid, gemtuzumab ozogamicin, imatinib mesylate, rituximab, and a bevy of signal transduction inhibitors and therapeutic monoclonal antibodies. Other new agents, such as liposomal daunorubicin, PEG-asparaginase, or clofarabine, represent chemical modifications of established antileukemic drugs. Increasingly, molecular profiling will be used to guide the development and application of new drugs.
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PMID:New agents in the treatment of childhood leukemias and myelodysplastic syndromes. 1622 75

A novel thermosensitive macromolecular prodrug of 5-fluorouracil (5-FU) was synthesized using cyclotriphosphazene, and its thermosensitivity, degradability, and in vitro antitumor activity were studied. A series of alpha-substituted glycine derivatives of 5-FU containing carboxylic groups were prepared, and cyclotriphosphazenes with amino groups were synthesized via the stepwise substitution of hexachlorocyclotriphosphazene (NPCl(2))(3) with methoxy-poly(ethylene glycol) (MPEG) or alkoxy ethylene oxide and lysine ethyl ester (LysOEt). The coupling reaction of the two derivatives, and their subsequent deprotection, yielded a thermosenstive 5-FU-cyclotriphosphazene conjugate, which exhibited a unique octopus-shaped molecular structure, in which the three hydrophilic PEG groups (or alkoxy ethylene oxides) were oriented in one direction, opposing the other three hydrophobic groups containing 5-FU, with respect to the trimer ring plane. This conjugate exhibited a reversible and thermosensitive phase transition in an aqueous medium, from soluble to insoluble states. The lower critical solution temperature (LCST) of the conjugate was controlled by substitution with different hydrophilic/hydrophobic side groups, and a few of the conjugates displayed LCSTs which were just below body temperature. This, of course, implies possible applications for local drug delivery by direct intratumoral injection. The conjugate exhibited gradual degradation at 37 degrees C in both neutral and acidic buffer solutions, and high temperature significantly facilitated its hydrolytic degradation. All of the conjugates displayed dose-dependent cytotoxicity against the leukemia L1210 cell line and exhibited more pronounced cytotoxic effects than did 5-FU.
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PMID:Novel thermosensitive 5-fluorouracil-cyclotriphosphazene conjugates: synthesis, thermosensitivity, degradability, and in vitro antitumor activity. 1628 51

Bacterial L-asparaginases have been used as therapeutic agents in the treatment of acute childhood lymphoblastic leukaemia for over 30 y. However, their use is limited owing to the glutaminase activity of the administered enzymes, which results in serious side effects. In contrast, L-asparaginase from Erwinia carotovora exhibits low glutaminase activity at physiological concentrations of L-asparagine and L-glutamine in the blood. Recombinant Er. carotovora L-asparaginase was crystallized in the presence of L-glutamate by the hanging-drop vapour-diffusion method using 10 mg ml(-1) purified enzyme, 16-18%(w/v) PEG 3350 and 0.2 M NaF. X-ray diffraction data were collected to 2.6 A at 293 K using an in-house rotating-anode generator. The crystals belong to the monoclinic P2(1) space group, with unit-cell parameters a = 78.0, b = 112.3, c = 78.7 A, beta = 101.9 degrees and a homotetramer in the crystallographic asymmetric unit. A molecular-replacement solution has been found and refinement is currently in progress. The crystal structure may provide leads towards protein-engineering efforts aimed at safer asparaginase administration in leukaemia treatment.
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PMID:Crystallization and preliminary crystallographic analysis of L-asparaginase from Erwinia carotovora. 1651 Oct 54

A novel transferrin receptor (TfR)-targeted liposomal formulation was synthesized and evaluated for the delivery of a phosphorothioate antisense oligodeoxyribonucleotide (ODN) (G3139, oblimerson sodium, or Genasense) to Bcl-2 in K562 leukemia cells. Liposomes composed of DC-Chol/egg PC/PEG-DSPE (25:73.5:1.5, mol/mol/mol) were loaded with G3139 with high efficiency (70-80%). To prepare targeted liposomes, transferrin was first coupled to PEG-DSPE and then incorporated into the bilayer by post-insertion. The liposomes had a mean diameter of 100 to 150 nm and exhibited colloidal stability for up to 8 weeks. Uptake of Tf-conjugated G3139-containing liposomes in TfR positive K562 cells was found to be more efficient than that of the non-targeted control formulation and could be blocked by excess free Tf. Treatment with Tf-conjugated liposomes resulted in Bcl-2 protein downregulation in K562 cells that was approximately 2-fold greater than with non-targeted liposomes (p<0.05) and 10-fold greater than with free G3139. Treatment with 2 microM G3139 in Tf-conjugated liposomes resulted in >80% reduction in Bcl-2 transcript. In addition, Tf-conjugated liposomal G3139-sensitized K562 cells to daunorubicin, lowering IC50 from 1.8 microM to 0.18 microM. In conclusion, Tf-conjugated liposomes are effective delivery vehicles for G3139 antisense oligos in TfR positive K562 cells and warrant further investigation as an in vivo oligo delivery vehicle.
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PMID:Efficient delivery of a Bcl-2-specific antisense oligodeoxyribonucleotide (G3139) via transferrin receptor-targeted liposomes. 1656 96

This study was aimed to investigate the specific anti-L615 leukemia cell immunity induced by L615/DC fused cell vaccine in vivo and in vitro. BM-derived DCs were generated from bone marrow of 615 mice by culturing for 9 - 10 days in culture medium supplemented with GM-CSF and IL-4. Irradiated L615 tumor cells were fused with DC by using PEG to form fused cell vaccine, with which 615 mice were immunized. After immunization, the specific proliferation ability and cytotoxicity against L615 leukemia cells in vitro were examined by MTT and LDH methods. Anti-leukemia effect of fused cell vaccine in vivo was studied by observing the immunotherapy effects on L615 tumor-bearing mice. The results showed that fully mature and functional bone marrow-derived DC were obtained. L615/DC fused cell vaccine could elicit potent specific proliferation response of spleen T cells from immunized mice when contacting with the same antigen at the second time, and could also elicit the effective cytotoxic activity against L615 leukemia cells in vitro, which were significantly different from other groups. In vivo the average survival time of the tumor-bearing mice received immunotherapy with L615/DC fused cell vaccine was 25.7 +/- 1 days, and one fourth of treated tumor-bearing mice survived for long time, but the mice of control group died all, their average of survival time was 17.5 +/- 1 days. The immunized mice survived with no evidence of recurrence when exposed to the second attack of lethal dose of living L615 cells 2 months later. It is concluded that L615/DC fused cell vaccine can improve the immunogenecity of L615 and induce effectively the specific anti-leukemia immunity against L615 leukemia cells to eliminate the residual leukemia cells, prolong the survival time and induce the immune memory to avoid the relapse. Thus, the fused cell vaccine may be an attractive strategy for malignance immunotherapy.
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PMID:[Anti-leukemia immunity induced by dendritic cells fused with L615 tumor cells]. 1663 13

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