Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the translocation breakpoint t(15;17) (q22;q21) in acute promyelocytic leukemia (APL) occurs within the retinoic acid receptor-alpha (RARA) gene, the expression of many genes normally regulated by RARA may be affected by this translocation. To identify genes that may be aberrantly expressed in APL, a subtraction cDNA library of an APL patient with t(15;17) was constructed. A cDNA, pRD1, specifically expressed in APL was identified. DNA sequence analysis of pRD1 showed that this gene is similar to the DNA sequence of annexin VIII, a gene which encodes a vascular anticoagulant. The annexin VIII gene was assigned to chromosome 10, which indicates that specific expression of this gene in APL is not directly involved in the t(15;17) breakpoint region. We have analyzed the expression of annexin VIII gene in nine t(15;17)-positive APL patients and one APL patient with a chromosome 17q-abnormality. We found that all APL samples expressed high levels of the annexin VIII gene. Expression of the annexin VIII gene in all other leukemias, including acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and acute lymphoblastic leukemia, was undetectable, except in one patient with acute myelogenous leukemia in which a very low level of expression was detected. Annexin VIII is highly expressed in the APL cell line, NB4. Its expression was significantly reduced after 8 hours of all-trans retinoic acid (ATRA) treatment, whereas the expression of RARA increased several-fold within 4 hours postinduction. Thus, increased expression of RARA preceded the downregulation of annexin VIII after ATRA induction, suggesting an inverse relationship between RARA and annexin VIII expression. Since increased expression of the fusion transcript was seen after ATRA induction and an APL without a t(15;17) translocation expressed high levels of annexin VIII, it appears that increased expression of annexin VIII in APL is not related to the fusion transcript. Therefore, dysregulation of the RARA gene may be related to the overexpression of annexin VIII in APL.
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PMID:Specific expression of the annexin VIII gene in acute promyelocytic leukemia. 131 14

Since initial studies identifying the important role of vitamin A and its derivatives (retinoids) in maintaining the integrity of epithelial tissues, these compounds have served as paradigms for experimental studies exploring the pharmacologic modification of carcinogenesis. Retinoids have clearly been shown to inhibit chemically induced mammary and urothelial carcinogenesis in experimental animals. Prohibitive toxicity of the parent compound, vitamin A, led to a systematic search for synthetic derivatives with an improved therapeutic index. More than 1500 such compounds have been synthesized, many retaining chemopreventive potential, but with less toxicity. Although several anecdotal reports confirming therapeutic benefits of cis-retinoic acid in patients with acute promyelocytic leukemia and myelodysplastic syndromes appeared in the late 1970s and early 1980s, the remarkable studies of Huang and his colleagues in China in 1988 reporting complete remissions in patients with this uncommon variety of acute myelogenous leukemia with the transisomer of retinoic acid (all-trans-retinoic acid) led to a resurgence of interest in the retinoids as differentiating agents for the prevention and therapy of cancer. Furthermore, molecular studies showing DNA rearrangements of the alpha nuclear receptor for retinoic acid located on chromosome 17 in patients with acute promyelocytic leukemia, a disease invariably associated with a translocation between chromosomes 15 and 17, provided a direct connection between an altered nuclear receptor and the development of a human malignancy. The retinoids also may have important beneficial effects in prevention of recurrent malignancies once the primary tumor has been treated, such as in squamous cell carcinoma of the head and neck. Because retinoids appear to be less effective in inducing differentiation in nonpromyelocytic leukemia cells, investigators have conducted a number of studies to exploit potential synergism between retinoids and other differentiating agents or biologic effectors. Differentiation therapy and chemoprevention are attractive alternative approaches to intensive cytotoxic chemotherapy. It is now clear that retinoids represent one class of compounds with which it may be possible to reverse the progression of malignant disease and prevent carcinogenesis.
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PMID:Retinoids in cancer treatment. 144 94

The current treatment of acute myelogenous leukemia is far from satisfactory despite some recent advances. This review focuses on current strategies designed to improve treatment outcome. With advances in molecular biology, the definition of a complete remission should be redefined as a molecular remission where any abnormal gene rearrangement has disappeared or a clonal remission with morphologic characteristics of a complete remission, but with detectable genetics or molecular abnormalities. Abnormal gene rearrangements permit the detection of minimal residual disease, the significance of which remains to be determined. New drug development remains an important area of research and several new drugs are active in acute myelogenous leukemia. These include etoposide, idarubicin, mitoxantrone and carboplatin. Various combinations are undergoing clinical trials. Prognostic factors which predict for outcome include phenotyping, cytogenetics, cytokinetics, drug resistance and age. Proto-oncogene expression as a predictor of response is under investigation. Post-induction therapy remains controversial and approaches have included allogeneic bone marrow transplantation, autologous bone marrow transplantation with or without purging, intensive consolidation and maintenance programs. The superiority of one approach over the other has not been firmly established. Differentiating agents such as all-trans retinoic acid, and growth factors, the latter for supportive care, or recruitment of leukemic cells into the cycle are being investigated. Understanding the mechanisms of drug resistance should lead to the development of new approaches. Thus, with knowledge generated in many areas, the future should bring increasing success in treating AML.
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PMID:Strategies in the treatment of acute myelogenous leukemia. 146 23

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

Numerous clinical trials in adult patients with newly diagnosed acute myelogenous leukemia indicate that the survival rate is approximately 20%. A limited number of favorable prognostic features have been identified; patients who present with specific cytogenetic abnormalities such as t(15;17), t(8;21) and inv (16) tend to have survival rates approaching 40%. However, such patients constitute only a small proportion of the total denominator and it has therefore been a major focus of scientific endeavor to develop new drugs for the treatment of this disease. A wide variety of agents have undergone preliminary testing in this regard and include both natural substances such as homoherringtonine, a drug that has demonstrated modest complete remission rates in this disease and all-trans retinoic acid, a compound that has revolutionized the treatment of acute promyelocytic leukemia. This review will put in perspective some of the newer drugs for the treatment of acute myelogenous leukemia and allow for some conclusions to be drawn as to their impact in the treatment of this disease.
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PMID:New drugs in acute myelogenous leukemia: a review. 156 32

Recent work has shown that acute promyelocytic leukemia (APL) cells have a characteristic translocation involving the retinoic acid receptor on chromosome 17 and the myl protein on chromosome 15. Patients with APL respond to the administration of all-trans-retinoic acid. A cell line with t15;17 (NB4) has recently been reported; this line responds to all-trans-retinoic acid with differentiation. There is also a recent report showing that all-trans-retinoic acid is more active than cis-retinoic acid in inducing differentiation in freshly obtained APL cells. All-trans-retinoic and cis-retinoic acid are compared for their effects on growth in culture of freshly obtained AML cells, cell lines without t15;17, and NB4 cells. While all of these AML populations responded to both forms of retinoic acid, NB4 cells only were much more sensitive to all-trans-retinoic acid compared to cis-retinoic acid. The difference was seen when the NB4 cells were exposed in suspension and not when colony-formation in methylcellulose was used as an end point. Both forms of retinoic acid increased the sensitivity of blast cells to cytosine arabinoside; for NB4 cells, the sensitization was much greater when all-trans-retinoic acid was used rather than cis-retinoic acid. We conclude that the increased effects of all-trans-retinoic acid are specific for APL cells, and that a major effect of retinoic acid is on blast stem cell self-renewal.
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PMID:Comparison of the effects of all-trans and cis-retinoic acid on the blast stem cells of acute myeloblastic leukemia in culture. 162 85

We have recently demonstrated that all-trans retinoic acid (RA), the active metabolite of vitamin A, is an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (AML3). We have further shown that, in these AML3 cells, the gene of the retinoic acid receptor-alpha (RAR alpha) is translocated from chromosome 17 to chromosome 15, and fused to a new gene, PLM. This results in the expression of both normal and chimeric RAR alpha transcripts in AML3 cells. The PLM-RAR alpha protein may account for the impairment of differentiation and thus leukemogenesis, but not for the paradoxical efficacy of RA in these cells. In an attempt to elucidate RA's differentiative effect in AML3 patients, the present work examined the in vitro and in vivo modulation of the normal RAR alpha transcripts by all-trans RA in seven cases of AML3. In all samples, Northern blot analysis revealed a low expression of the two normal RAR alpha transcripts compared with other human myeloid leukemic cells. No modulation was observed after 4-8 d of in vivo therapy with all-trans RA 45 mg/m2 per d. In vitro incubation with all-trans RA, however, increased the level of expression of the normal RAR alpha transcripts in AML3 cells but not in other AML leukemic subtypes. This modulation of the two normal RAR alpha transcripts appeared to be an early and primary event of RA's differentiating effect. We therefore suggest that up-regulation of the normal RAR alpha gene expression by pharmacological concentrations of all-trans RA may restore the normal differentiation pathway in these cells.
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PMID:All-trans retinoic acid modulates the retinoic acid receptor-alpha in promyelocytic cells. 166 1

One proposed therapeutic application of granulocyte colony-stimulating factor (G-CSF) is in differentiation induction therapy of myelodysplastic states (MDS) or acute myeloid leukemia (AML). G-CSF however has a substantial growth including effect which limits its potential as a differentiation inducing agent. We have therefore made a systematic search for agents which might restrain the proliferative effects of G-CSF whilst retaining the differentiation stimulus. Of all the agents we have tested on human bone marrow progenitor cells: (6-thioguanine, all-trans retinoic acid, vincristine, recombinant human alpha-2b and gamma-interferon) only the latter abolished the stimulation of cell growth and retained, or possibly increased, the differentiation effect of G-CSF. The antiproliferative drugs 6-thioguanine and vincristine both antagonized the neutrophil-granulocyte differentiation inducing action of G-CSF. Retinoic acid and alpha-2b interferon both had weak effects on proliferation and failed to enhance differentiation. These results suggest that it may be possible, by combining G-CSF with a suitable second agent, to utilize its substantial differentiation inducing effect without incurring the potentially hazardous effects of increased leukemic cell growth.
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PMID:Dissociation of the proliferation and differentiation stimuli of granulocyte colony-stimulating factor (G-CSF). 169 Mar 19

All-trans-retinoic acid, hexamethylene bisacetamide and 5-azacytidine are inducers of granulocytic differentiation of HL-60 human myeloid leukaemic cells, which eventually leads to inhibition of cell proliferation. The effect of graded concentrations of all-trans-retinoic acid (RA) (1 nM-1 microM), hexamethylene bisacetamide (HMBA) (0.5-4 mM) and/or 5-azacytidine (5azaC) (1 nM-1 mM), alone and in combination with each other on colony formation and growth of HL-60 cells was studied in agar capillary clonogenic micro assays in order to identify new potential therapeutic regimens for elderly patients with acute myeloid leukaemia. ED90 concentrations, inducing 90% inhibition of colony formation for RA, HMBA and 5azaC, were 128 nM, 2.7 mM and 40 microM, respectively. The drug interactions between these differentiating agents were analysed by Berenbaum's general algebraic solution. The combinations: RA + HMBA, 5azaC + HMBA and RA + 5azaC were significantly synergistic in inhibiting HL-60 colony formation. Their interaction indices were 0.62, 0.83, and 0.97, respectively, at a specific effect level of 15%. The addition of 1 mM HMBA to 100 nM 5azaC- and 1 nM RA-treated cultures significantly increased the colony-formation inhibition from only 2.6% and 7.0% to 46.4%, and 43.1%, respectively. Also, HMBA showed marked synergism with RA and 5azaC in inhibiting colony growth. The interaction indices (I) of HMBA + RA and HMBA + 5azaC were 0.013 and 0.009, respectively, at the same specific level of 15%. Moreover, the triple combination of RA + HMBA + 5azaC showed synergism in inhibiting both the colony formation (I = 0.7) and colony growth (I = 0.4) at the same specific level of 15%. Since RA, HMBA and 5azaC were effective when administered alone in phase I clinical trials of myeloid leukaemic patients, their synergistic combinations could provide shorter and less toxic courses of treatment in elderly myeloid leukaemic patients. I is less than 1, = 1 or greater than 1 in synergistic, additive or antagonistic interactions, respectively.
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PMID:Synergistic interactions between differentiation-inducing agents in inhibiting the proliferation of HL-60 human myeloid leukaemia cells in clonogenic micro assays. 170 42

AML cells were cultured free of serum with G-CSF in combination with all-trans-retinoic acid (RA), prostaglandin E2 or 8-bromocyclic AMP to see whether the maturation blockade of these cells could be overcome. The combination G-CSF + RA was most effective in inducing morphologic maturation, i.e. in 7/10 cases. Morphological alterations in response to G-CSF + RA indicated progression of the cells along the granulocytic pathway towards metamyelocytes and granulocytes. However, morphologically mature AML cells remained negative for myeloperoxidase and Sudan black stainings, indicators of granulocytic maturation. Chloracetate esterase positivity and CD15 membrane antigens became expressed on cultured AML cells, i.e. on unstimulated and G-CSF/RA exposed blasts. Ingestion of latex beads and reduction of nitroblue tetrazolium salt occurred in cultured AML cells regardless of the presence of inducers. In almost all cases clonogenic cells persisted after exposure to G-CSF + RA suggesting that subpopulations of immature cells escaped the action of these inducers. Thus although G-CSF + RA were capable of inducing maturation of AML cells along the granulocytic lineage, maturation was incomplete and the effect was evident in a subfraction of the cells only.
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PMID:Induction of granulocytic maturation in acute myeloid leukemia by G-CSF and retinoic acid. 171 Jul 46


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