Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

More than 50% cure can be obtained with allogeneic bone marrow transplantation (BMT) when patients are transplanted in first remission of AML and ALL or chronic phase of CML. On the other hand, considerable progress has been made recently in treating acute leukemia with chemotherapy. Recent studies of intensive chemotherapy in adults with AML report approximately 40-50% 3-year disease-free survival (DFS). Accordingly, several prospective randomized clinical trials have been conducted on the use of BMT versus intensive chemotherapy in the treatment of AML. Significant differences in DFS were found only in a few studies though the results of BMT appear to be comparable or superior to chemotherapy. Therefore, the overall advantage of BMT in first remission AML is smaller than expected. We should know not whether to transplant or to perform chemotherapy, but rather whether to transplant in first remission or to perform chemotherapy first and reserve transplantation as salvage therapy. Recently acute promyelocytic leukemia has been successfully treated with differentiation therapy using all-trans retinoic acid. Low-dose aclarubicin has also been reported to be effective as differentiation therapy in some patients with myelodysplastic syndrome and atypical AML. With the advance of molecular biology of cytokines, several of them are now available for clinical use. G-CSF, GM-CSF and M-CSF are potent stimulators for the granulocyte-macrophage production; they are very effective for accelerating hematologic recovery after chemotherapy-induced myelosuppression or BMT. Interferon-alpha (IFN-alpha) has been used in the several studies. Furthermore, Ph chromosome positivity can be reduced with long-term administration of IFN-alpha; Ph-positive clone can be undetectable in some patients. Thus, IFN-alpha will be the choice of treatment for CML even if BMT is planned.
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PMID:[New trends in the treatment of leukemia]. 177 64

Bone marrow cells from 15 patients with myelodysplastic syndromes and 2 with acute myeloid leukemia were incubated in vitro with all-trans-retinoic acid (RA), 1,25-dihydroxy vitamin D3 (D3), cytosine arabinoside (ara-C) and alpha-interferon (IFN). 3H-thymidine incorporation (3H-TdR), differentiation and clonal growth were studied. D3 was found to be the most effective inducer of differentiation and differentiation was correlated with a decreased 3H-TdR. Differentiation with one of the inducers was significantly correlated to differentiation with any of the other inducers. Patterns of differentiation and spontaneous and D3-induced 3H-TdR were used to divide the patients into 3 different groups. In the first group, 5 patients with extremely low spontaneous 3H-TdR and differentiation in combination with a slightly increased 3H-TdR after induction differed from all other patients by a higher percentage of bone marrow blast and a more pronounced pancytopenia. The two other groups had a high spontaneous 3H-TdR but differed with respect to the D3-induced differentiation which was absent in one group (n = 6) and present in the other (n = 5). The two groups showed no difference in the clinical features.
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PMID:Effects of retinoic acid, 1,25-dihydroxyvitamin D3, cytosine arabinoside and alpha-interferon on bone marrow cells from patients with myelodysplastic syndromes. 261 68

Five retinoid analogues differ in their effects on the growth of CFU-GM from normal human marrow. At concentrations above 10(-6) M all have inhibitory activity. This is maximal with 13-cis-retinoic acid. At lower concentrations the effect of retinoids is usually to reduce clone size rather than clone numbers though 10(-8)-10(-7) M etretinate increases clone size. The incubation of marrow cultures in the presence of 10(-6) M all-trans retinoic acid showed that in normal subjects colony counts are never reduced to less than 45% of the control value and total clone counts to less than 70% of the control value. In cultures from patients with myelodysplastic syndrome 20 out of 34 cases showed a greater inhibition of colony numbers than normal and 14 out of 35 cases showed a greater reduction in total clone numbers than normal. The results suggest that CFU-GM from some patients with myelodysplastic syndrome may have a greater sensitivity than normal to the inhibitory effect of retinoic acid.
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PMID:The effect of retinoids on CFU-GM from normal subjects and patients with myelodysplastic syndrome. 397 Aug 48

Since all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF) not only enhance proliferation and differentiation of normal myeloid cells but also synergistically promote the differentiation of myeloid leukemic blast cells in vitro, we have started a pilot study of combined treatment with ATRA and G-CSF in patients with myelodysplastic syndrome, to analyze the effect of these drugs on hematopoietic differentiation. ATRA was given at 45 mg/m2/day p.o. from week 1-12 and G-CSF at 5 micrograms/kg/day s.c. from week 5-12 with dose modifications according to the absolute neutrophil counts (ANC). A total of 15 patients, predominantly with refractory anemia, were treated. During initial ATRA therapy, a bilineage response with increases of both ANC and platelet counts occurred in three patients. During combined ATRA/G-CSF therapy, ANC increased in all patients, and platelets increased in three out of 14 evaluable patients. An increase in hemoglobin concentration and a decrease in transfusion requirements occurred in one patient each. In the bone marrow, the myeloid-to-erythroid ratio increased during ATRA treatment and remained increased during concomitant G-CSF administration, while the maturation index of myeloid cells increased only in response to ATRA therapy, but returned to baseline during ATRA/G-CSF treatment. Cytogenetic analysis demonstrated persistence of the abnormal clones in all patients. The number of circulating progenitor cells CFU-GM increased in all patients studied. Serum concentrations of the soluble TNF receptor and IL-2 receptor both increased, while TNF-alpha--already elevated prior to therapy--and soluble ICAM-1 concentrations did not significantly change. Adverse effects included dermatitis and cheilosis in most patients, and a drop in platelet counts related to G-CSF in one patient. The pilot study demonstrates that the combination treatment with ATRA/G-CSF is well tolerated, leading to normalization of ANC in most, and improvement of platelets and red blood cells in a subgroup of patients.
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PMID:Effect of combination therapy with all-trans-retinoic acid and recombinant human granulocyte colony-stimulating factor in patients with myelodysplastic syndromes. 751 Mar 54

Variants of the t(15;17)(q22;q12-q21) chromosomal rearrangement associated with acute promyelocytic leukemia (APL) have been previously described and they frequently involve either chromosome 15 and/or 17. Previously we reported a rare variant t(11;17). We now describe two patients with myelodysplastic syndrome (MDS) that transformed to APL-like leukemia. Both had trisomy 11 at the diagnosis of APL-like leukemia. Following treatment for APL, patient 1 reverted to MDS and showed a normal karyotype. When leukemia recurred, his bone marrow karyotype was 47,XY,t(4;11), +11,der(22)t(1;22). Both patients were treated with all-trans retinoic acid (ATRA) for APL for 5 weeks, but failed to respond. The karyotype of patient 1 after ATRA treatment was 46,XY,t(4;11); the trisomy 11 had been lost and the bone marrow was replaced with immature myeloblasts without promyelocytes. In patient 2, the karyotype remained the same as at diagnosis, i.e., 47,X,-Y,dir ins(4;7),del(5), +6,del(7), +8, + 11,-18. Molecular analysis by reverse transcriptase PCR analysis showed the presence of wild type retinoic acid receptor alpha (RARA) and the absence of the PML-RARA chimeric gene associated with t(15;17). Additional analysis of PLZF, a new zinc finger gene associated with t(11;17), also showed the absence of this hybrid gene. These data support the concept that APL is a heterogeneous disorder and that variants with chromosome 11 rearrangement exist that do not respond to ATRA.
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PMID:Myelodysplastic syndrome transforming to acute promyelocytic-like leukemia with trisomy and rearrangement of chromosome 11. 751 69

Differentiation induction therapy is used in myelodysplastic syndromes (MDS) to improve maturation defects and to restore impaired function of malignant cells. To this end, 18 patients with MDS received either a combination therapy consisting in study 1 of all-trans retinoic acid (ATRA) and granulocyte-colony stimulating factor (G-CSF), or in study 2 of a combination with ATRA, G-CSF, erythropoietin (Epo) and tocopherol. The ANC increased in 19/20 patients in both studies, whereas an increase in haemoglobin concentration, platelet counts or reduction of transfusion requirement was seen in only 8/20 patients, correlating strongly with good BFU-E growth (P < 0.001). To assess the role of accessory cells in the modulation of the haemopoietic response to treatment, we analysed the capacity of peripheral blood monocytes to secrete cytokines (IL-1 beta, IL-6, IL-8, TNF alpha). Secretion of all cytokines was significantly reduced before therapy when compared with healthy controls, but increased during therapy, reaching normal levels for IL-8. These data indicate that a combination therapy with ATRA and cytokines improves impaired cytokine secretion from monocytes and induces a multilineage clinical response in a subgroup of MDS patients characterized by an almost intact erythroid compartment. In contrast, induction of TNF alpha might be responsible for treatment failure.
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PMID:Changes in erythroid progenitor cell and accessory cell compartments in patients with myelodysplastic syndromes during treatment with all-trans retinoic acid and haemopoietic growth factors. 855 92

The ability of induction of differentiation of leukemia cells was first proved by cultured leukemia cells, and such ability has been also confirmed clinically as a result of observation of the dramatic effect of all-trans retinoic acid on acute promyelocytic leukemia and the usefulness of low-dose of ara-C therapy for acute myeloid leukemia. We studied differentiation induction of primary cultured bone marrow cells from myelodysplastic syndrome (MDS) patients by ara-C and VP16 with or without addition of G-CSF. We also studied clinical efficacy of differentiation therapy in 56 patients with MDS. Differentiation induction effects were observed in 3 of 14 patients treated with G-CSF in combination with low-dose of ara-C or low-dose of VP16. In addition, high-dose methylprednisolone therapy, GM-CSF and anabolic steroid therapy also showed similar effect on refractory anemia, even in a few patients. Since these results suggested the usefulness of differentiation therapy of MDS, it is earnestly hoped that more effective therapy, including a concomitant use of cytokine, might be established as soon as possible.
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PMID:[Differentiation therapy for myelodysplastic syndrome]. 768 64

Clinical trials of differentiation therapy on MDS with retinoic acid are reviewed, and it is discussed whether the differentiation therapy with this drug has scientific relevance for MDS. 13-Cis retinoic acid (13-CRA) may have moderate effect on 20-30% of patients with MDS. In general, the responses are short and toxicity is significant. Since the responses may take at least three weeks and sometimes several months to occur, only patients with a relatively indolent clinical course of MDS would be suitable candidates for this therapy. However, a placebo-controlled prospective randomized study could not confirm the effectiveness of this retinoic acid on MDS. There are only a few clinical trials of all-trans retinoic acid (ATRA) for treatment of MDS. ATRA may have a moderate effect on MDS, but no such a remarkable effect shown on acute promyelocytic leukemia. A placebo-controlled randomized study as having been conducted in 13-CRA is definitely needed to confirm the effectiveness of ATRA on MDS.
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PMID:Differentiation therapy of myelodysplastic syndromes with retinoic acid. 781 99

Myelodysplastic syndrome (MDS)-derived leukemia cell line P39/Tsugane could be induced to apoptosis by a variety of agents including metabolic inhibitors, a calcium ionophore and differentiation-inducing agents. As evaluated by characteristic morphological changes and oligonucleosomal lengths DNA ladder, the levels of apoptosis in P39 cells induced by actinomycin D, or A23187, were far greater than in other myeloid lines examined in this study. When 22-oxa-1 alpha, 25(OH)2D3 (D3), dimethyl sulfoxide (DMSO) and all-trans retinoic acid (RA) were used as differentiation-inducers, varying degrees of apoptosis were seen. D3 induced monocytoid differentiation, but not apoptosis above the control level. On the other hand, RA induced profound apoptosis concomitant with the progressive expression of differentiation markers. Studies on morphology, functions and phenotypes of P39 cells exposed to differentiation inducers suggest that the incidence of apoptosis was not affected by the process of differentiation, but cells in the process of varying degrees of differentiation may die via apoptosis. Moreover, RA-treated P39 cells are unique in the simultaneous occurrence of profound apoptosis and differentiation. We propose that RA-treated P39 differentiation model is ideally suited for the study of MDS.
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PMID:Marked apoptosis of human myelomonocytic leukemia cell line P39: significance of cellular differentiation. 812 49


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