Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D02003 (NBT)
1,323 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 74 year-old woman, who had been diagnosed as AML (M3) in poor condition, was treated with Retinol Palmitate (Chocola-A, 150,000 unit/m2 per os, after informed consent. An increase of white blood cells (neutrophil) counts was observed after 7 days. After 4 weeks, WBC counts were increased to 20,700/microliters (neutrophil counts 6,400/microliters) Maturation tendency of leukemic cells was also proved in the bone marrow. In vitro studies showed that morphological differentiation was recognizable in cultured leukemic cells treated with 10(-6)M all-trans retinoic acid after 6 days, but not in controls. Responses in the NBT reduction test were slightly less than in the clinical study. The administration of Retinol Palmitate may be a new regimen to treat AML (M3) in aged patients in poor condition.
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PMID:[Differentiating effect of oral administration of retinol palmitate (Chocola-A) for an aged AML (M3) with severe complications]. 146 82

Twenty-four patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (45 to 100 mg/m2/day). Of these, eight cases had been either nonresponsive or resistant to previous chemotherapy; the other 16 cases were previously untreated. All patients attained complete remission without developing bone marrow hypoplasia. Bone marrow suspension cultures were studied in 15 of the 24 patients. Fourteen of these patients had morphological maturation in response to the retinoic acid (1 mumol/L). Chloroacetate esterase and alpha-naphthyl acetate esterase staining as well as electronmicroscopic examination confirmed that retinoic acid-induced cells differentiated to granulocytes with increased functional maturation (as measured by nitroblue tetrazolium reduction, NBT). The single nonresponder to retinoic acid in vitro was resistant to treatment with retinoic acid but attained complete remission after addition of low-dose cytosine arabinoside (ara-C). During the course of therapy, none of the patients showed any abnormalities in the coagulation parameters we measured, suggesting an absence of any subclinical disseminated intravascular coagulation. The only side effects consisted of mild dryness of the lips and skin, with occasional headaches and digestive symptoms. Eight patients have relapsed after 2 to 5 months of complete remission. The others remain in complete remission at 1+ to 11+ months and are still being followed up. We conclude that all-trans retinoic acid is an effective inducer for attaining complete remission in APL.
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PMID:Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. 316 95

Using a system of sequential daughter cell transfers in semisolid medium, we have analyzed self-renewal and differentiation of human promyelocytic leukemia cells (HL60) in presence of all-trans retinoic acid and human placental conditioned medium (HPCM). We find that retinoic acid induces coordinated losses of self-renewal potential which are followed by phenotypic differentiation. The latter occurs as an all-or-none event and is reversible in the presence of HPCM. Thus, HL60 cells that apparently had terminally differentiated (as estimated by the ability to reduce nitroblue tetrazolium [NBT]) can lose their differentiation marker and reenter the proliferative pool.
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PMID:Human placental conditioned medium reverses apparent commitment to differentiation of human promyelocytic leukemia cells (HL60). 386 98

The effect of cytokines on the proliferation and differentiation of leukemia cells from 5 patients with acute promyelocytic leukemia (APL) was examined. Interleukin-1 beta (IL-1), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) augmented uptake of 3H-thymidine into the DNA of APL cells in a dose-dependent manner in all cases. This stimulatory effect was pronounced in some, but not all, cells treated with all-trans retinoic acid (ATRA). However, nitroblue tetrazolium-reducing activity was induced in a concentration-dependent manner by ATRA in all cases. The cytokines greatly enhanced NBT reduction of APL cells treated with ATRA, and a mixture of cytokines was more effective than a single cytokine. Although GM-CSF, IL-3 and IL-1 significantly modulated the ATRA-induced morphological changes, they did not induce CD14 expression, a typical marker of monocytic differentiation. In the presence of ATRA, GM-CSF potentiated production and secretion of tumor necrosis factor-alpha (TNF) in response to lipopolysaccharide, as well as interferon-gamma which is a potent inducer of monocytic differentiation in APL cells. On the other hand, production of TNF in ATRA-treated cells was not affected by G-CSF which significantly enhanced granulocytic differentiation. The effect of cytokines on APL cell differentiation should be considered in ATRA treatment for APL patients. Potentiation of cytokine production in APL cells associated with myelomonocytic differentiation is noteworthy in the pathogenesis of "retinoic acid syndrome".
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PMID:Effect of cytokines on the proliferation and differentiation of acute promyelocytic leukemia cells: possible relationship to the development of "retinoic acid syndrome". 752 Nov 52

HL-60 cells can be induced to differentiate into mature granulocytic cells in a continuous exposure to all-trans retinoic acid (RA) for at least 96 h. In this study, RA was removed after being exposed to HL-60 cells for 12-96h. Then the cells were reincubated in a fresh medium without drug for additional 48-144h and their differentiation markers such as NBT reduction, morphological changes and cytokinetic characteristics were studied. The results demonstrated that once exposed continuously to 1.0 mumol/L RA for at least 48h, the HL-60 cells would proceed to terminal differentiation: about 60-90 percent of the cells became NBT positive, 40-80 percent of cells exhibited decreased nucleus/cytoplasm ratio and marked reduction in the number of nucleoli and displayed matured granulocytic morphology. Cytokinetic studies demonstrated 48-85 percent of cells arrested in G1 phase, which is typical for differentiated cells. However, if the cells were exposed to RA for less than 48h, they would not show differentiation phenotype. These results indicate that 48h exposure is critical for HL-60 cell differentiation induced by RA, and the cell differentiation induced by RA is irreversible and RA-independent.
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PMID:[Chronological characteristics of retinoic acid-induced HL-60 cell differentiation]. 780 52

We have tested the effect of several bile acids on the proliferation and differentiation of the HL60 human promyelocytic leukemia cell line in vitro. Deoxycholate, chenodeoxycholate and lithocholic acid caused dose-dependent inhibition of cell proliferation and induction of differentiation along the monocyte/macrophage pathway as determined by morphology, NBT test, non-specific esterase, and staining by monoclonal antibodies against specific cell-surface antigens. Optimal effects were obtained at 100, 75, and 60 microM of the 3 bile acids respectively. Cell-cycle flow-cytometric analysis showed that a substantial fraction of HL60 cells accumulated at the G0/G1 transition. Protein-kinase-C inhibitors such as sphinganine and H-7 inhibited the differentiation-inducing effect of bile acids, suggesting a possible role for PKC in this regulation. When bile acids were combined with non-effective concentrations of all-trans retinoic acid, enhancement of the monocytic differentiation of THP-1 human leukemia cells was observed. Our findings demonstrate induction of tumor-cell differentiation by bile acids, compounds that present minimal undesirable effects in humans.
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PMID:Inhibition of proliferation and induction of monocytic differentiation on HL60 human promyelocytic leukemia cells treated with bile acids in vitro. 792 7

Recent studies have shown that a high proportion of patients with acute promyelocytic leukemia (APL) achieve complete remission after treatment with all-trans retinoic acid (RA). Nevertheless, despite an initial good response, most patients that received continuous treatment with all-trans RA relapse and develop RA-resistant disease. The 9-cis RA is a high-affinity ligand for retinoid X receptors (RXRs) and also binds efficiently to retinoic acid receptors (RARs); all-trans RA is a ligand for RARs. Both alone are able to induce differentiation of wild-type HL-60 cells. We found that neither all-trans RA nor 9-cis RA (< 2 x 10(-6) mol/L) induced differentiation of RA-resistant HL-60 cells into either mature granulocytes or monocytes. However, morphologic differentiation of the RA-resistant HL-60 cells was induced by 10(-6) mol/L all-trans RA combined with various concentrations (10(-12) to 10(-6) mol/L) of 9-cis RA. Electron microscopic examination also confirmed that the combination of both retinoids induced RA-resistant HL-60 cells to differentiate to mature granulocytes. Functional analysis of differentiation (NBT reduction activity) confirmed the necessity of both analogs to induce differentiation. Also, expression of myeloid-specific differentiation antigens (CD11b and CD14) as well as migration inhibitory factor-related protein (MRP)-8/14 mRNAs were upregulated only in the presence of both retinoids in a dose-dependent manner. In these conditions 3H-thymidine incorporation was inhibited and numbers of viable cells were decreased, suggesting that all-trans RA with 9-cis RA may inhibit cell growth and induce differentiation of RA-resistant HL-60 cells into mature granulocytes. These studies suggest that 9-cis RA in combination with all-trans RA is an effective inducer of RA-resistant HL-60 cells and may have implications for both the biology of retinoids and clinical treatment of RA-resistant acute myelogenous leukemia, including APL patients.
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PMID:Novel retinoic acid, 9-cis retinoic acid, in combination with all-trans retinoic acid is an effective inducer of differentiation of retinoic acid-resistant HL-60 cells. 819 64

Acute promyelocytic leukemia (APL) is an interesting model for cancer research because of the presence of the specific PML-RARalpha fusion gene associated with the clinical response to retinoic acid differentiation therapy. To better understand and improve differentiation induction with retinoic acid, we have established a human APL-ascites model in SCID mice using the NB4 human APL cell line. NB4 (1 x 10(6) cells) were transplanted into the peritoneum (IP) of SCID mice for 1 month. NB4 ascites cells (A-NB4) appeared, which were then engrafted in SCID mice periodically for 18 passages at an interval of 3 to 4 weeks with a 100% success rate of tumor induction. The mean survival times of SCID mice transplanted with 1 x 10(6) A-NB4 cells was 21.6 +/- 2.3 days. Analysis of the biologic characteristics of ninth passage NB4 ascitic cells was performed and they were found to have the morphologic, immunologic, cytogenetic, and molecular features of cultured NB4 cells. Furthermore, A-NB4 cells were capable of differentiating when treated with all-trans retinoic acid (ATRA), as manifested by enhanced NBT reduction and CD11b expression. In vivo treatment with ATRA in SCID mice for 4 days also increased NBT reduction by A-NB4 cells. ATRA treatment significantly prolonged survival time in the group after transplantation (28.1 +/- 6.8 to 29.1 +/- 8.4 days) compared with the control (P < .001). Furthermore, treatment with adriamycin, an effective chemotherapeutic drug in APL, had a strong growth suppressive effect on A-NB4 cells. These results demonstrate that this SCID-APL (NB4 ascites cells) model is a useful preclinical system for evaluating new or known drugs in the treatment of APL.
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PMID:Establishment of a human acute promyelocytic leukemia-ascites model in SCID mice. 860 58

All-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). Nevertheless, most of these patients develop RA resistance and relapse. The mechanisms of RA resistance by APL cells are still unclear. To understand the characteristics of human leukemia, human leukemic cell lines are useful tools for study. APL cells have a strikingly low proliferation potential in vitro; thus, only one APL cell line has been established. We developed a novel APL cell line (UF-1) from a patient clinically resistant to all-trans RA. Cell surface markers in the UF-1 cells were positive for CD7, CD13, CD33, and CD38. Cytogenetic analyses revealed additional abnormalities, 46XX, add(1)(q44), add(6)(q12), add(7)(q36), t(15;17) (q21;q21). Molecular analyses showed a PML/RAR alpha fusion transcript. Sequence analysis of the RAR alpha gene in RA-resistant HL-60 cells disclosed a point mutation in codon 411 (C to T substitution), whereas UF-1 cells showed the normal sequence. All-trans RA did not change morphological features of the cell, NBT reduction activity, or their expression of CD11b antigens as determined by FACS analysis except at 10(-6) mol/L. RA also did not alter the growth curve of the cells as determined by the MTT assay. These findings suggest that the UF-1 cell is the first permanent cell line with spontaneous RA-resistant APL cells. This RA-resistant APL cell line may be a useful model for molecular studies on the block of leukemic cell differentiation and as a means to investigate the mechanisms of RA resistance.
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PMID:Establishment and characterization of a novel acute promyelocytic leukemia cell line (UF-1) with retinoic acid-resistant features. 878 40

Differentiation therapy for acute promyelocytic leukemia (APL) using all-trans-retinoic acid (ATRA) has improved the prognosis of the disease. ATRA therapy also causes a newly recognized clinical syndrome, the "retinoic acid syndrome" (RAS), which can be successfully managed with dexamethasone. Because aberrant function of maturing leukemic granulocytes may cause this syndrome, and because dexamethasone is useful clinically, we studied functional properties of maturing HL60 cells cultured in the presence and absence of dexamethasone. HL60 cells were cultured for 4 days with ATRA and studied daily to determine acquisition of mature neutrophil-like properties including phagocytosis, NBT reduction, actin polymerization, chemotaxis and adhesion molecule expression. Undifferentiated HL60 cells could not polymerize actin or reduce NBT, and exhibited only a minimal ability to undergo chemotaxis or ingest latex beads. Following 4 days of maturation with ATRA, the cells would increase F-actin content in response to interleukin-8, ingest latex beads, migrate in a chemotaxis chamber, reduce NBT, and express CD11b. When dexamethasone was added to the cells in culture, there was no major enhancement or suppression of these properties. We also studied the effect of dexamethasone on functional properties of normal neutrophils and found minimal if any effect on their function. Overall, these studies suggest that in vitro, dexamethasone has little effect on the function of leukemic and normal granulocytes. To further investigate the pathophysiology of the retinoic acid syndrome, future studies may need to use endothelial cells, cytokines, or granulocytes obtained from APL patients.
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PMID:The effect of dexamethasone on functional properties of HL60 cells during all-trans retinoic acid induced differentiation. Are there implications for the retinoic acid syndrome? 893 54


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