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)

Vitamin A and its analogues (retinoids) affect normal and malignant hematopoietic cells. We examined the effect of retinoids on the clonal growth in vitro of myeloid leukemia cells. Retinoic acid inhibited the clonal growth of the KG-1, acute myeloblastic leukemia, and the HL-60, acute promyelocytic leukemia, human cell lines. The KG-1 cells were extremely sensitive to retinoic acid, with 50% of the colonies inhibited by 2.4-nM concentrations of the drug. A 50% growth inhibition of HL-60 was achieved by 25 nM retinoic acid. Complete inhibition of growth of both leukemia cell lines was seen with 1 microM retinoic acid. Exposure of KG-1 cells to retinoic acid for only 3-5 d was sufficient to inhibit all clonal growth. The all-trans and 13-cis forms of retinoic acid were equally effective in inhibiting proliferation. Retinal, retinyl acetate, and retinol (vitamin A) were less potent inhibitors. Clonal growth of the human K562 and mouse M-1 myeloid leukemic cell lines was not affected by 10 microM retinoic acid. Retinoic acid also inhibited the clonal growth of leukemia cells from five of seven patients with acute myeloid leukemia. Retinoic acid at concentrations of 5 nM to 0.3 microM inhibited 50% clonal growth, and 1 microM retinoic acid inhibited 64-98% of the leukemic colonies. The inhibition of clonal growth of KG-1 and HL-60 cell lines and of leukemic cells from two patients was not associated with the presence of a specific cytoplasmic retinoic acid-binding protein. Our study suggests that retinoic acid may prove to be effective in the treatment of human myeloid leukemia.
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PMID:Retinoic acid. Inhibition of the clonal growth of human myeloid leukemia cells. 627 39

Induction of differentiation of the human promyelocytic leukemia cell line, HL-60, by dimethyl sulfoxide was analyzed for a requirement for cell replication. The ability of HL-60 cells to undergo terminal granulocytic differentiation as judged by nitroblue tetrazolium reduction, phagocytosis, and morphological criteria was not impaired by a total block in cellular proliferation. Retinoic acid, actinomycin D, and butyric acid also induced differentiation of HL-60 cells in the absence of cell growth. These results and the earlier demonstration that phorbol ester-induced macrophage differentiation of HL-60 occurred independently of DNA synthesis indicate that in these leukemic cells there is a dissociation of proliferation and maturation. The ability of retinoic acid to enhance differentiation of HL-60 cells was not altered in the presence of various growth-inhibiting concentrations of two clinically useful chemotherapeutic agents: hydroxyurea and 1-beta-D-arabinofuranosylcytosine. These results suggest that combination therapy in a program aimed at both inhibiting proliferation and inducing differentiation of leukemia cells could be beneficial.
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PMID:Terminal differentiation of the human promyelocytic leukemia cell line, HL-60, in the absence of cell proliferation. 695 59

Retinoic acid (RA) is a vitamin A derivative with striking effects on development and cell differentiation. The identification of three RA receptors (RAR alpha, beta and gamma) as members of the nuclear receptor superfamily led to important insights into the molecular mechanism of action of retinoids. The nuclear receptors, that also include receptors for steroid hormone, vitamin D3 and thyroid hormone act as ligand-inducible transcription factors and are characterized by the presence of two well conserved DNA- and hormone-binding domains. One of the most intriguing properties of RA is its ability to induce in vivo differentiation of acute promyelocytic leukaemia (APL) cells into mature granulocytes, leading to morphological complete remissions. We and others have shown that the t(15;17) translocation specifically associated with APL fuses an as yet unidentified gene, named PML, to the retinoic acid receptor alpha locus. The resulting PML-RAR alpha hybrid protein that retains most of the functional domains of parental proteins exhibits altered transactivating functions when compared to the wild-type receptor; however the biological significance of this property in the transforming phenotype is still obscure. PML, whose function is unknown, belongs to a novel family of nuclear proteins characterized by the presence of a Cys/His-rich motif, named a RING finger, that include RNA-binding proteins, transcription factors and oncoproteins. A dimerization domain within PML is able to mediate the formation of PML-RAR alpha homodimers that can bind to target sequences with distinct DNA binding properties if compared with RAR alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The t(15;17) translocation in acute promyelocytic leukemia. 767 45

Retinoic acid (RA) is capable of inducing the differentiation of various myelomonocytic cell lines. During this differentiation process, the levels of c-myb expression decline, suggesting that the RA receptor (RAR) may act in part by down-regulating this proto-oncogene. We have now investigated whether the RAR can also inhibit the function of Myb proteins themselves. We have found that transcriptional activation of a Myb-responsive reporter gene can be inhibited by RA in a human monocytic cell line. This inhibition could not be overcome by the expression of exogenous Myb. The RAR did not interfere with DNA binding by Myb proteins in vitro, suggesting that the functional inhibition occurs at the level of transcriptional activation. To determine the biological relevance of the inhibition of Myb proteins by the RAR, we have used v-myb-transformed monoblasts. These cells differentiate into macrophages in the presence of phorbol ester (tetradecanoyl phorbol acetate [TPA]) but are normally unresponsive to RA treatment. The introduction of an inducible, exogenous RAR alpha into v-myb-transformed monoblasts permitted an RA-dependent differentiation into macrophage-like cells similar to those induced by TPA. These results demonstrate that transformation by v-myb is recessive to RAR alpha and imply that many types of non-RA-responsive leukemia cells may become responsive following the introduction of the RAR.
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PMID:Retinoic acid receptor alpha suppresses transformation by v-myb. 773 32

Retinoic acid and hydrocortisone (HC) have been shown to regulate the drug sensitivity of the blast cells of acute myeloblastic leukemia (AML). We asked if the proto-oncogene bcl-2 played a role in this regulation. As target cells we used the continuous lines, OCI/AML-1, OCI/AML-2 or OCI/AML-5; expression of bcl-2 can be detected by Northern analysis of RNA from OCI/AML-2 or OCI/AML-5 cells; bcl-2 expression can be found in OCI/AML-1 cells only by using RT-PCR. Exposure of OCI/AML-2 or OCI/AML-5 cells to retinoic acid (all-trans retinoic acid, ATRA) led to a down-regulation of bcl-2 expression that was first seen after 2 h of exposure and was complete after a day. The down-regulation could be prevented by exposing the cells to ara-C either before or after ATRA; decrease in bcl-2 protein was moderate and only obvious after 36 h of ATRA treatment. Nuclear run-on experiments provided evidence that bcl-2 down-regulation was occurring at transcriptional and post-translational levels. Since bcl-2 is considered to have anti-oxidant activity, we tested the sensitivity of the three cell lines to H2O2; we found that OCI/AML-1, the line with very low bcl-2 expression, was a 100-fold more H2O2-sensitive than OCI/AML-2 or OCI/AML-5, where bcl-2 expression can be detected readily. We then asked if H2O2 sensitivity could be regulated. We found that exposure of cells to HC before H2O2 was protective while ATRA after peroxide treatment increased killing; this is the same pattern of regulation observed when AML blasts are exposed to HC before, or ATRA after ara-C. Finally, we asked whether N-acetylcysteine (NAC), a known radical scavenger would protect cells against ara-C killing. Significant protection was observed when NAC was given before drug, but not if given after drug. NAC protection against ara-C killing was seen for OCI/AML-1 and 2 cells, but not for OCI/AML-5 cells. We interpret the results as follows: ara-C kills cells in two ways: first, directly, by incorporation into DNA and chain termination; second, indirectly, by inducing the production of toxic radicals. Bcl-2 reduces the oxidant activity of such radicals, and is protective. ATRA regulates ara-C toxicity by its action on bcl-2. Left unexplained are the action of HC, which does not affect bcl-2 expression and the mechanism by which ara-C prevents down-regulation of bcl-2 by ATRA.
Leukemia 1995 May
PMID:Mechanism of cytosine arabinoside toxicity to the blast cells of acute myeloblastic leukemia: involvement of free radicals. 776 41

Tretinoin is effective in acute promyelocytic leukaemia in adults. Data about its efficacy and safety in children are limited. We have treated 9 children with tretinoin at 45 mg/m2 per day. Pseudotumour cerebri or hyperleucocytosis occurred in 5 patients. Retinoic acid syndrome was seen in 3 cases. 1 of 2 children who developed hyperleucocytosis, pseudotumour cerebri, and retinoic acid syndrome died despite steroids and mechanical ventilation. Complete remissions with tretinoin alone were achieved in 15 patients. All 8 surviving children received consolidation chemotherapy. Our experience with tretinoin therapy suggests that toxicity is frequent in children.
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PMID:Tretinoin toxicity in children with acute promyelocytic leukaemia. 790 75

Cell surface expression of leukosialin (sialophorin, CD43 antigen) on human neoplastic hematopoietic cell lines K-562, U-937, HL-60 and REH was determined with the aid of a new CD43 monoclonal antibody (Bra7G) by the immunochemical (radioimmunoprecipitation, immunoblotting) and immunocytofluorometric techniques. Interferon-gamma and TNF-alpha were utilized as the "physiological" inducers of differentiation-associated markers. The "non-physiological" inducer phorbol ester PMA induced down-regulation of leukosialin cell surface expression on immature erythroid-myeloid leukemia cell line K-562, but up-regulation of CD43 antigen on the promyelocyte leukemia cell line HL-60 and, to a lesser extent on the monocyte-like U-937 and CALLA+ ALL cell line REH. Retinoic acid down-regulated leukosialin on both U-937 monocyte-like cells and the CALLA+ ALL cell line REH. In contrast to these data, interferon-gamma, TNF-alpha, retinoic acid and 1,25(OH)2-vitamin D3 induced the up-regulation of leukosialin in a promyelocytic leukemia cell line HL-60.
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PMID:Modulation of leukosialin (sialophorin, CD43 antigen) on the cell surface of human hematopoietic cell lines induced by cytokins, retinoic acid and 1,25(OH)2-vitamin D3. 835 Sep 52

A retrospective analysis was done on 43 patients with acute promyelocytic leukemia (APL) at our hospital from June 1987 to August 1992. All-trans retinoic acid was used to induce these patients to differentiation. In the early period of induction there were risks of severe hemorrhage, which was the main cause of early death. Treatments combined with platelets and heparin or aminomethylbenzoic (PAMBA) were given to patients with abnormal coagulation. As a result only 4 out of 43 patients died of intracranial bleeding at 4-12 days when their white blood cell (WBC) counts peaked. The combination of retinoic acid (RA) and HA chemotherapy could reduce hyperleukocytosis during the RA induction course. None of 7 patients died at early stage with this treatment combination. Our studies showed that it could predict the onset of remission at early stage through observations on the successive changes of karyotypes and morphology of the bone marrow and peripheral blood cells. Our studies also showed that the growth of CFU-F could be inhibited by RA. We think that it may play a role in the RA-induced differentiation. In 4 years of follow-up the overall leukemia-free survival (LFS) was 80% with a relapse rate of 45%. Thirty-five patients out of 43 cases were still alive in remission, and one was alive in relapse. All 11 out of 43 patients relapsed within 3 years, but the relapses occurred later, after 3 years duration of remission (P < .01). Retinoic acid failed to induce 5 patients who relapsed with the continuation treatment of RA and chemotherapy alternatively. In order to overcome the resistance to RA, the continuation treatment of simple chemotherapy had been administered following CR. Two cases achieved remission in this way. The difference of resistant events to RA reached significance between these 2 groups of different continuation treatment.
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PMID:Four years' experience with the treatment of all-trans retinoic acid in acute promyelocytic leukemia. 835 33

Retinoic acid is known to induce differentiation of human myeloid leukemia cells in vitro. Recently, all-trans retinoic acid has been used to induce remissions in patients with acute promyelocytic leukemia, probably through differentiation of the leukemia cells. Myeloblastin (mbn) is a protease that has been identified in the human leukemia cell line HL-60. Downregulation of this protease can inhibit proliferation and induce differentiation of HL-60-derived leukemia cells. Here we have investigated the regulation of mbn messenger RNA (mRNA) expression in two human leukemia cell lines, HL-60 and NB4, treated with all-trans retinoic acid. Under this treatment, downregulation of mbn mRNA was observed in both cell lines, but was considerably delayed in NB4 cells that carry the t(15;17) translocation characteristic of acute promyelocytic leukemia. We have found that multiple mechanisms were involved in the control of mbn mRNA expression. These mechanisms were different in HL-60 and NB4 cells. Our results show that in HL-60 cells, all-trans retinoic acid rapidly decreased transcription of mbn. In contrast, in the t(15;17)-positive NB4 cells treated with all-trans retinoic acid, upregulation of mbn mRNA expression was followed by a late downregulation, both achieved via posttranscriptional mechanisms.
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PMID:Regulation of myeloblastin messenger RNA expression in myeloid leukemia cells treated with all-trans retinoic acid. 842 65

Retinoic acid exhibits effects on the proliferation and differentiation of many hematopoietic cells. Cellular responsiveness to retinoic acid (RA) is conferred through two distinct classes of nuclear receptors, the RA receptors (RARs) and the retinoid X receptors (RXRs). The RARs bind to both 9-cis- and all-trans-RAs, but 9-cis-RA alone directly binds and activates RXR. This suggested that 9-cis-RA could have expanded hematopoietic activities as compared with all-trans-RA. We compared the abilities of 9-cis- and all-trans-RAs to induce differentiation and inhibit proliferation of three acute myelogenous leukemia (AML) cell lines and fresh leukemic cells from 28 patients and found that: (1) 9-cis-RA in general was more potent than all-trans-RA in suppressing the clonal growth of two AML cell lines and 17 AML samples from patients, including four from individuals with acute promyelocytic leukemia (APL). Eleven leukemic samples, including three from patients with chronic myelogenous or chronic myelomonocytic leukemia, were relatively refractory to both retinoids. (2) The range of activities of both retinoids was similar except that the clonal growth of samples from three AML patients were inhibited by 9-cis-RA, but not by all-trans-RA. (3) Both retinoids inhibited the clonal proliferation of leukemia cells without necessarily inducing their differentiation; in fact, the only fresh AML cells that were able to undergo differentiation were from patients with APL and one individual with M2 AML. (4) Both retinoids enhanced myeloid and erythroid clonal growth from normal individuals, and 9-cis-RA showed slightly more stimulation of the myeloid clonal growth than did the all-trans-RA. Our study suggests that 9-cis-RA is worthy of further study for the treatment of selected individuals with AML.
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PMID:9-cis-retinoic acid: effects on normal and leukemic hematopoiesis in vitro. 842 82


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