Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent in vitro studies indicate that bone marrow mesenchymal elements, residing in close proximity to hematopoietic cell populations, elaborate a network of cytokines that are, at least partially, responsible for modulating the growth and maturation of the latter compartment. Leukemia inhibitory factor (LIF), a molecule with both positive and negative regulatory activities, has been implicated in murine embryogenesis and hematopoiesis. We demonstrate that cultured normal human bone marrow stromal cells constitutively express LIF message. Further, exposure of these cells to other hematopoietic modulators including interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) (but not interferon-alpha [IFN alpha]) increases the level of LIF RNA. Interestingly, cultured stromal cells derived from three of four patients with chronic myelogenous leukemia showed enhanced LIF expression. These observations suggest that LIF may participate, either alone or through interaction with other cytokines, in the bone marrow microenvironment-mediated influence on both normal and malignant hematopoietic processes.
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PMID:Constitutive expression of leukemia inhibitory factor RNA by human bone marrow stromal cells and modulation by IL-1, TNF-alpha, and TGF-beta. 170 8

Hematopoietic cells from the malignant clone in chronic myelogenous leukemia (CML) maintain and expand a proliferative advantage over normal hematopoietic cells within the bone marrow. This advantage is often ameliorated or reversed in vivo by IFN alpha. Based upon earlier studies suggesting decreased adhesiveness of CML progenitor cells, we asked whether CML progenitor cells are deficient in their expression of the cytoadhesion molecule lymphocyte function antigen-3 (LFA-3, CD58) which is normally expressed on hematopoietic progenitors. Progenitor cells from untreated CML patients showed greatly reduced or absent LFA-3 expression, whereas progenitors from patients treated with IFN alpha in vivo or in vitro expressed surface LFA-3 at more normal levels. LFA-3-deficient CML progenitor cells were unable to stimulate normal regulatory proliferative responses in autologous T cells. We hypothesize that IFN alpha-sensitive LFA-3 deficiency reflects a cell surface cytoadhesion defect which may help explain adhesive abnormalities of CML progenitor cells in vitro and clonal proliferation in vivo.
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PMID:Interferon-alpha restores the deficient expression of the cytoadhesion molecule lymphocyte function antigen-3 by chronic myelogenous leukemia progenitor cells. 172 27

A 60-year-old woman was admitted to our hospital because of gastric ulcer, anemia, and leukocytosis in November 1984. Blood cell counts on admission were as follows: RBC 407 x 10(4)/microliters, Hb 9.8 g/dl, WBC 33,000/microliters (baso 8%, eo 7%, myelo 11%, meta 2%, stab 4%, seg 54%), Plt 93.7 x 10(4)/microliters. Bone marrow showed hypercellular and myeloid hyperplasia. She was diagnosed as Ph1-chromosome positive chronic myelogenous leukemia. She received natural interferon-alpha at the dosage of 600 x 10(4) IU daily for 22 days from January 14, 1985. After March 1985, she has been given intermittent administration of interferon once in 10 to 20 days, and maintained normal blood cell counts. Cytogenetic improvement was seen on 35 months after the start of IFN and complete suppression of Ph1 chromosome was observed at July 1990 (66 months after).
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PMID:[Intermittent administration of natural interferon-alpha for over 5 years induced complete suppression of Philadelphia chromosome in a patient with myelogenous leukemia]. 177 60

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

In 6 women aged 38 to 68 years with thrombocythaemia during chronic myeloid leukaemia (4 cases), myelofibrosis (1 case), and idiopathic thrombocythaemia (1 case) the effects of recombinant human alpha-interferon (Intron A, rh IFN alpha -2b, Schering) were studied. The drug was given to all patients subcutaneously in one daily dose of 3 x 10(6) u, every day for 3 weeks, and then in the same doses twice weekly for 2 weeks (5 cases) and for 14 weeks (1 case). Intron A caused in all cases a fall of peripheral blood platelet count by 37% to 65.5% (mean 50%) in relation to the initial count (532 - 1,453 x 10(9)/l). The fall of the platelet count occurred usually after 7-10 days of this treatment, and the lowest count was noted usually after 24 days (10 to 42 days). During the treatment in 4 cases the peripheral leucocyte count dropped as well by 20-70%. In no cases exacerbation of chronic myeloid leukaemia was noted, and in the patient with myelofibrosis the enlarged spleen shrunk somewhat. These results of treatment and follow-up of patients with thrombocythaemia treated with Intron A indicate a significant although short-lasting effect of platelet count fall limited, however, to the time of the treatment. Side effects of the drug included mainly febrile conditions, myalgia and arthralgia.
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PMID:[Effectiveness of interferon alfa in different stages of thrombocythemia (preliminary report)]. 182 71

The therapeutic efficacy and toxicity of alpha-interferon (alpha-IFN) (Roferon, Hoffmann-La Roche, Inc., Nutley, NJ) were determined in 15 children (age range, 6 to 20 years) with Philadelphia chromosome-positive chronic myelocytic leukemia (Ph+ CML). All patients had received cytoreductive therapy with either hydroxyurea (n = 13) or busulfan (n = 1) or both (n = 1) for 6 weeks to 46 months (median, 7 months) before beginning alpha-IFN therapy at a dose of 5 x 10(6) U/m2/d intramuscularly. This dose was escalated to 10 x 10(6) U/m2/d if leukemia was inadequately controlled. Ten children had a hematologic response, with nine showing a reduction in the percentage of Ph+ marrow cells, including four who had no detectable Ph+ cells in marrow samples collected 48 to 204 weeks after the initiation of therapy. Two of 15 patients remain free of Ph+ cells. Therapy was discontinued before week 104 in ten patients because of the following: (1) early hematologic responses without a decrease in Ph+ cells (three patients); (2) early resistant disease (one patient); (3) blast crisis (one patient); (4) progressive disease (two patients); (5) seizure attributed to high-dose alpha-IFN (one patient); or (6) an inadequate trial of alpha-IFN caused by aseptic necrosis or poor compliance (two patients). The most common side effects were mild and have included fever, malaise, headache, myalgias, and pain at the injection site. Adverse events causing interruption of therapy were seizures, aseptic necrosis, and myelofibrosis. alpha-IFN stabilizes the chronic phase of Ph+ CML in some children, is adequately tolerated when administered at a dose of 2.5 to 5 x 10(6) U/m2/d intramuscularly, and results in a significant decrease in the proportion of Ph+ metaphases in some patients. alpha-IFN in combination with an effective cytoreductive agent or agents appears worthy of further clinical testing in this disease.
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PMID:Response to alpha-interferon in children with Philadelphia chromosome-positive chronic myelocytic leukemia. 183 44

In a pilot study, 32 patients with Philadelphia chromosome-positive chronic myelogenous leukemia were treated with intensive chemotherapy induction followed by interferon-alpha (IFN-A) maintenance. Intensive chemotherapy consisted of three cycles of daunorubicin 120 mg/m2 on day 1, cytarabine 80 mg/m2 daily for 10 days, vincristine 2 mg on day 1, and prednisone 100 mg daily for 5 days (DOAP). Maintenance therapy with IFN-A at a doses of 3 x 10(6) to 5 x 10(6) units/m2 daily was adjusted according to counts and toxicity. The outcome of patients was compared with a matched historic population of 64 patients treated with IFN-A alone. Overall, 60% of patients had a cytogenetic response (partial or complete) with induction chemotherapy, but only eight (25%) had a sustained cytogenetic response with IFN-A maintenance. After a median follow-up of 67 months, the 6-year survival rate of the 32 patients was 58%, compared with 36% for the matched historic group (P = 0.084). The incidence of lymphoid blastic transformation in the two groups was 25% and 48%, respectively (P = 0.10) and durable cytogenetic responses, 25% and 19%, respectively (P = 0.48). In summary, the addition of intensive chemotherapy induction to IFN-A maintenance does not improve the survival rate, incidence of lymphoid blastic transformation, or incidence of durable cytogenetic response compared with the results achieved with IFN-A therapy alone.
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PMID:Intensive chemotherapy induction followed by interferon-alpha maintenance in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. 187 71

Four patients with Philadelphia chromosome positive CML were treated with 18-42 x 10(6) IU of purified natural leukocyte IFN-alpha per week, after high-dose chemotherapy for blast phase and attainment of 2nd chronic phase. The second blast phase occurred within 3 months in 3 patients, but one patient is still in second chronic phase after 22 months of treatment. Treatment consisted of interferon only during the first year, and interferon in combination with hydroxyurea during the second year. During the second year suppression of the Philadelphia chromosome was seen in one patient, with 20% Philadelphia negative bone marrow metaphases. The toxicity of purified natural leukocyte IFN-alpha was similar to the toxicity of recombinant IFN-alpha. Antibodies to IFN-alpha were not detected in any patient.
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PMID:Leukocyte interferon in the treatment of chronic myelogenous leukemia in second chronic phase. 189 79

A 19-year-old man with Philadelphia-positive chronic myelogenous leukemia treated with interferon-alpha (IFN-alpha) therapy for 45 months had systemic lupus erythematosus disease features: malar rash, migratory arthralgias, elevated antinuclear antibodies, elevated antinative DNA, hypocomplementemia, lymphopenia, and proteinuria. After discontinuation of the IFN and initiation of corticosteroids, there was gradual recovery of symptoms, a decline in antinative DNA and antinuclear antibodies to normal levels, and a decrease in proteinuria. The potential association between IFN therapy and the development of systemic lupus erythematosus, and the role of IFN in other autoimmune diseases, is discussed.
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PMID:Development of systemic lupus erythematosus after interferon therapy for chronic myelogenous leukemia. 189 53

Primitive blast colony-forming cells (BI-CFC) from chronic myeloid leukemia (CML) patients are defective in their attachment to bone marrow-derived stromal cells compared with normal BI-CFC. We investigated the effect of recombinant interferon-alpha 2a (IFN-alpha) on this interaction between hematopoietic progenitor cells and bone marrow-derived stromal cells by culturing normal stromal cells with IFN-alpha (50 to 5,000 U/mL). At 50 U/mL we found that: (1) the capacity of stromal cells to bind two types of CML primitive progenitor cells (BI-CFC and long-term culture-initiating cells) was increased; and (2) the amount of sulfated glycosaminoglycans (GAGs) in the stromal layer was increased. However, sulfated GAGs were not directly involved in binding CML BI-CFC, unlike binding by normal BI-CFC, which is sulfated GAG-dependent. Neuraminidase-treated control stromal cells bound an increased number of CML BI-CFC, reproducing the effect of IFN-alpha, whereas the binding to IFN-alpha-treated stromal cells was unaffected by neuraminidase treatment. Thus, the enhanced attachment by primitive CML progenitor cells to INF-alpha-treated stromal cells might be due to changes in the neuraminic acid composition in the stromal cell layer. Our in vitro evidence may provide insights into the mechanism of action of IFN-alpha in vivo. Prolonged administration may alter the marrow microenvironment in some patients such that it can restrain the aberrant proliferation of Philadelphia chromosome (Ph)-positive stem cells while permitting Ph-negative stem cells to function normally.
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PMID:Interferon-alpha overrides the deficient adhesion of chronic myeloid leukemia primitive progenitor cells to bone marrow stromal cells. 190 52


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