Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activation in leukemia has been less well characterized than in other malignancies. However, the increased tendency to bleeding and tissue infiltration by leukemic cells are processes in which plasminogen activation may be involved. We have examined plasma and the peripheral blood mononuclear cell fraction from 80 patients including 53 patients with newly diagnosed acute leukemia and 27 patients with other hematological disorders as well as 21 healthy controls. In 28 of 29 examined patients with acute myeloid leukemia (AML) and in two of three patients with hybrid leukemia we found urokinase receptor (uPAR) on the cell surface, while most (7/9) samples from patients with acute lymphoblastic leukemia (ALL) were negative for uPAR. The plasma mean value for soluble uPAR (suPAR) was significantly elevated in patients with AML and ALL. In AML the highest values were found in patients who had residual disease after several cycles of chemotherapy. Compared to controls the uPA antigen levels in patient plasmas were elevated and decreased along with uPAR during treatment. Our results suggest that cell surface uPAR may be a useful marker for leukemia classification and in our material a high level of plasma suPAR correlated with resistance to chemotherapy in AML.
 ...
PMID:Blast cell-surface and plasma soluble urokinase receptor in acute leukemia patients: relationship to classification and response to therapy. 1036 41

Plasminogen activation is implicated in solid tumour growth, invasion and metatastic spread. However, little is known about its role in leukaemia. We investigated the production by leukaemic cells of plasminogen activators [urokinase (uPA) and tissue-type PA (tPA)], cell surface receptor for uPA (uPAR) and PA inhibitors (PAI-1 and PAI-2). Leukaemic cells from 37 patients [26 with acute myeloid leukaemia (AML) and 11 with acute lymphoid leukaemia (ALL)] were analysed for mRNA content and enzymatic activities. High levels of uPA mRNA were found in M1, M2, M3 and M4-M5 AMLs, whereas tPA mRNA was not detected in any of the analysed cases. uPAR mRNA was confined to subtypes M4-M5. PAI-1 mRNA was detected in M3 and M4-M5. PAI-2 mRNA was found predominantly in M2 and M4-M5. SDS-PAGE/zymography analyses of cell extracts and supernatants after 24 and 48 h of culture confirmed the production of active uPA by AML cells (mainly M4-M5). but not by ALL. The finding of uPA, uPAR, PAI-1 and PAI-2 synthesized by leukaemic cells suggests that plasminogen activation may contribute to the invasive behaviour of these cells, the fibrinolytic imbalance observed in leukaemic patients and the differentiation and proliferation of M4-M5 by interaction of uPA with uPAR.
 ...
PMID:Plasminogen activation in human acute leukaemias. 1055 1

Plasminogen activator inhibitor 1 (PAI-1) has been found to be a bad prognostic factor in a number of tumours but the reason has not been fully explained. The human prostate cancer cell line PC-3 and the human promyelocytic leukaemia cell line HL-60 were used in this study to determine the effect of PAI-1 on spontaneous and induced apoptosis in culture. Apoptosis was induced with camptothecin or etoposide. Addition of a stable variant of PAI-1 or wild-type PAI-1 to these cells resulted in a significant inhibition of apoptosis. In contrast, both the latent form of PAI-1 and the stable variant of PAI-1 inactivated by a specific neutralizing monoclonal antibody, or the stable variant of PAI-1 in a complex with recombinant urokinase did not inhibit apoptosis. This indicated that the inhibitory activity of PAI-1 was required for its anti-apoptotic effect but the urokinase-type plasminogen activator receptor was not involved. These findings provide an explanation for the bad prognostic correlation of high PAI-1 levels in tumours. The anti-apoptotic effect was also found in non-tumoural cells including human umbilical vein endothelial cells and the benign human breast epithelial cell line MCF-10A, suggesting that this is a novel physiologic function of PAI-1.
 ...
PMID:Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. 1081 7

Two patients with cerebral sinus thrombosis were successfully treated with neuroradiological intervention procedures, one with local thrombolysis and the other with mechanical thrombosuction using a hydrolyser catheter. The first patient, a 20-year-old woman, was treated with asparaginase for acute lymphatic leukaemia. She lapsed into coma with extensor posturing due to superior sagittal and right transverse sinus thrombosis. She recovered completely after local thrombolysis with 2,940,000 units urokinase, administered over a period of 40 hours. The second patient was a 29-year-old man who presented with clinical deterioration after seizures due to superior sagittal, left transverse and straight sinus thrombosis. A CT-scan demonstrated bilateral haemorrhagic cerebral infarctions. Since the risk of haemorrhage during thrombolysis with urokinase was considered to be high, mechanical thrombosuction with a hydrolyser catheter was performed. This procedure took only 4 hours. The patient recovered completely in two weeks. These cases add further evidence to the effectiveness of thrombolysis and thrombosuction in selected patients with severe cerebral sinus thrombosis.
 ...
PMID:[Neuroradiologic intervention in two patients with cerebral sinus thrombosis]. 1115 59

Current research suggests that the appearance of endometrial integrins and pinopode appearance signal the opening of the receptive phase of the endometrium. These integrins may be activated by the interleukin-1 system (IL-1). IL-1beta, expressed by the blastocyst, induces vascular endothelial growth factor (VEGF) which, in turn, promotes angiogenesis and integrin expression in endometrial cells. The IL-1 system also triggers the expression of gamma interferon (IFN-gamma) from T lymphocytes. Decidual natural killer (NK) lymphocytes interact with invading trophoblast to generate leukaemia inhibitory factor (LIF). LIF induces uPA and gelatinase, enzymes which play a crucial role in trophoblastic invasion. Progesterone is a potent inhibitor of LIF, while oestrogen is a potent inducer. Oestrogen in serum reflects follicular IL-1beta level and correlates with the outcome of embryo transfer after in vitro fertilization (IVF). Progesterone induces nitric oxide (NO) synthesis in the decidua, and NO promotes local vasodilatation and uterine quiescenceMeasurement of placental protein 14 (PP14, glycodelin-A) in serum may be of value as a screening test for implantation potential. However, human chorionic gonadotrophin (hCG) remains the most reliable predictor of successful implantation and pregnancy viability. An ovulation + 14 hCG level < 50 IU/l is often predictive of a non-viable outcome, while an ovulation + 21 hCG of < 200 IU/l always indicates a non-viable pregnancy. hCG secretion by invading trophoblast appears to be negatively modulated by endothelin-1 (ET-1) and prostaglandin F(2alpha)(PGF2alpha), while tissue growth factors and collagenases are positive modulators of hCG expression.ProalphaC, an inhibin pro-monomer, may have some value in monitoring corpus luteum function. Inhibin A, activin A and follistatin all rises throughout pregnancy and peak at 36 weeks of gestation. Relaxin is another ovarian hormone that may have a role in predicting implantation. Relaxin induces placental protein 14 (PP14, glycodelin-A) expression in a receptive endometrium, and measurement of serum PP14 may be of value as a screening test for implantation potential.
 ...
PMID:Endocrinology of the peri-implantation period. 1102

Trimidox (3,4,5-trihydroxybenzohydroxamidoxime), a recently synthesized inhibitor of ribonucleotide reductase (RR), was shown to exert anti-proliferative activities in HL-60 and K562 human leukemia cell lines and to prolong the life span of mice inoculated with L1210 mouse leukemia cells. Here we test whether trimidox also exhibits anti-neoplastic properties in ovarian carcinoma cells. Since the mode of action of trimidox on cell fate has not been investigated so far, we addressed this unresolved item and find that this polyhydroxybenzoic acid derivative induces apoptosis of N.1 human ovarian carcinoma cells when tested in growth factor deprived medium. Utilizing an improved analysis, based on Hoechst 33258/propidium iodide double staining, apoptosis is quantified and discriminated from necrosis. Trimidox induces c-myc expression, which is indispensible for apoptosis of N.1 cells, and expression of plasminogen activator/urokinase type (upa), which supports the apoptotic process under more physiological conditions. Surprisingly, trimidox does not block dNTP synthesis in N.1 cells at the concentrations tested and, therefore, trimidox induces apoptosis independent of RR-inhibition. Like TNFalpha or benzamide riboside, which are also inducers of apoptosis of N.1 cells, trimidox also down-regulates the G1 cell cycle phosphatase cdc25A, whereas cyclin D1 becomes up-regulated. This report shows that trimidox destroys human ovarian carcinoma cells by inducing them to undergo apoptosis as well as corroborating previous investigations which demonstrated that apoptosis of these cells depends on c-myc over-expression when survival factors are withdrawn.
 ...
PMID:The ribonucleotide reductase inhibitor trimidox induces c-myc and apoptosis of human ovarian carcinoma cells. 1119 20

Implanted vascular access devices (ports) play a major role in the management of children with cystic fibrosis (CF) and many haematological conditions. With the expanding use of ports, new and more frequent complications are being encountered. To retrospectively review the complications associated with ports, the case notes of all patients who underwent insertion of a port between 1997 and 2000 were analysed. Details of the underlying disorder, type of vascular device, nature of use, and complications were recorded; 55 ports were inserted in 41 patients (a second port was required in 12, a third port in 2) during this period. Their underlying diagnoses were CF (11), haemophilia (4), haemolytic anaemias (2), immunological disorders (6), solid neoplasms (8), and leukaemia (10). Thirteen ports (24%) were removed and replaced for various complications: infection (2), blockage (4), leak (2), dislodgement (2), and malposition (3). Including four port-related problems managed conservatively (3 access problems managed by change in access technique; 1 blockage managed by urokinase), the over all complication rate was 31%. Ports thus have a high complication rate with long-term use. Selecting the right port system, proper installation of the port chamber, and efficient handling and maintenance by trained staff could prevent the vast majority of port-related complications.
 ...
PMID:Implanted vascular access devices (ports) in children: complications and their prevention. 1272 47

Tumor cell migration and metastasis in cancer are facilitated by interaction of the serine protease urokinase type plasminogen activator (uPA) with its receptor uPAR (CD 87). Overexpression of uPA and uPAR in cancer tissues is associated with a high incidence of disease recurrence and early death. In agreement with these findings, disruption of the protein-protein interaction between uPAR present on tumor cells and its ligand uPA evolved as an attractive intervention strategy to impair tumor growth and metastasis. For this, the uPAR antagonist cyclo[19,31][D-Cys(19)]-uPA(19)(-)(31) was optimized to efficiently interrupt binding of uPA to cellular uPAR. First, the disulfide bridge of this lead compound was shifted and then the modified peptide was shortened from the amino and carboxy terminus to generate cyclo[21,29][Cys(21,29)]-uPA(21)(-)(30). Next, cyclo[21,29][D-Cys(21)Cys(29)]-uPA(21)(-)(30) was yielded by changing the chirality of Cys(21) to D-Cys(21). For analysis of uPAR binding activity, we employed competitive flow cytofluorometric receptor binding assays, using FITC-uPA as the ligand and U937 promyeloid leukemia cells as the cellular source of uPAR. As demonstrated for cyclo[21,29][D-Cys(21)Cys(29)]-uPA(21)(-)(30), the achieved peptide modifications maintained receptor binding activity (IC(50) = 0.04 microM), which is close in order to that of the parent protein ligand, uPA (IC(50) = 0.01 microM). A detailed NMR analysis with restrained and free molecular dynamics calculations in explicit H(2)O exhibits a well-defined structure with characteristic features such as an omega-loop with two betaI-turns about Lys(3), Tyr(4), Ser(6), and Asn(7). Hydrophobic clustering of the side chains of Tyr(4), Phe(5), Ile(8), and Trp(10) is observed. Side chain mobility is analyzed with time-dependent distance restraints. The NMR structure of cyclo[21,29][D-Cys(21)Cys(29)]-uPA(21)(-)(30) is very similar to the previously reported structure of the amino terminal fragment of uPA. Systematic point mutations led to cyclo[21,29][D-Cys(21)Nle(23)Cys(29)]-uPA(21)(-)(30), which still binds to uPAR but is resistant to proteolytic cleavage, e.g., by the tumor-associated serine proteases uPA and plasmin, and is stable in blood serum or plasma. In conclusion, small cyclic peptides were created, which mimic the structure and activity of the binding epitope of uPA to uPAR and which may serve as novel therapeutic agents in cancer metastasis.
 ...
PMID:Synthesis, solution structure, and biological evaluation of urokinase type plasminogen activator (uPA)-derived receptor binding domain mimetics. 1240 9

In previous studies, we demonstrated that the diphtheria toxin-urokinase fusion protein DTAT was selectively toxic to acute myeloid leukemia (AML) cell lines overexpressing the CD87 urokinase receptor. In the present study, we analyzed the sensitivity of patient leukemic progenitors to DTAT and correlated the sensitivity with CD87 expression. We isolated leukemic blasts by density gradient centrifugation and performed immunophenotyping by flow cytometry and blast sensitivity measurements by inhibition of cell proliferation and colony formation in semisolid media. We found CD87 overexpression in 18 (25%) of 71 patient leukemic blast samples, including 18 (28%) of 64 myeloid malignancies and 0 (0%) of 7 lymphoid malignancies. DTAT was toxic to patient leukemic blasts by both proliferation inhibition (IC50 <or=1 nM DTAT in 18/69 evaluable samples) and colony formation inhibition (>85% inhibition by 10 nM DTAT in 11/41 evaluable samples). Only AML and chronic myeloid leukemia (CML) blast crisis blasts (18/61 [30%]) were sensitive to DTAT by the proliferation inhibition assay. Lymphoid leukemia and chronic phase CML/chronic myelomonocytic leukemia (CMML) progenitors were insensitive to DTAT by the proliferation inhibition assay (n = 7 and n = 3, respectively). Similarly, normal marrow progenitors were insensitive to DTAT by both proliferation inhibition (n = 2) and colony inhibition (n = 5) assays. The DTAT toxicity measured by both proliferation inhibition assay and colony inhibition assay correlated with CD87 density (p < 0.0001 and p = 0.001, respectively). DTAT toxicity results were similar for leukemic blasts measured by either of the two assays (p = 0.0002). This study provides the first evidence that a urokinase receptor targeted diphtheria fusion protein is toxic to patient AML blasts. The work also suggests that blast proliferation assays yield similar responses to leukemia colony-forming cell colony assays.
 ...
PMID:Malignant progenitors from patients with CD87+ acute myelogenous leukemia are sensitive to a diphtheria toxin-urokinase fusion protein. 1242 85

The inherited or acquired deregulation of protein kinase activity has been implicated in the pathogenesis of many human diseases, including cancer. Therefore, the inhibition of kinases has been proposed to be a promising strategy in the context of anti-cancer treatment. Many other kinases have been selected as drug discovery targets based on the prevalence of mutations, over-expression and unscheduled activation in human cancer. Of the various protein kinases chosen, Src family kinases are amongst the most extensively studied kinase oncogenes in academia and industry. This review focuses on our current understanding of the deregulation and role of Src family kinases in human cancer and leukemia. Recent data implicate the action of c-Src in cancer metastasis, mediated by up-regulation of various protease systems (calpain, uPA) as well as disruption of E-cadherin signalling. Moreover, novel roles of various Src family members in the development of human leukemia have been found. New insights into downstream signalling mechanisms, including the activation of STAT3, PDK1 and Akt, further corroborate the importance of Src family kinases in tumorigenesis and chemoresistance. Despite our rather clear understanding of Src family kinases as pro-oncogenes no Src family kinase inhibitor has entered a clinical trial so far. This review will discuss prerequisites to be fulfilled for clinically targeting c-Src and its homologues using small molecule drugs.
 ...
PMID:SRC family kinases: potential targets for the treatment of human cancer and leukemia. 1452 15


<< Previous 1 2 3 4 5 6 7 Next >>