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)

Unequivocally, complete remission (CR) is a prerequisite for the cure for acute leukemia. The history of drug therapy for acute leukemia has taught us that only after CR rates exceed 90% can a satisfactorily high cure rate be obtained, as is observed in acute lymphoblastic leukemia in children and acute promyelocytic leukemia (APL). In multicenter studies of adult acute myeloid leukemia (AML), CR rates hardly exceed 80% with currently available cytotoxic drugs, except for a small fraction of patients having AML with t(8;21) or inv(16). CR rates and survival of adult patients with AML in 4 studies by the Japan Adult Leukemia Study Group from 1987 to 1997 do not improve at all when appropriately adjusted. The remarkable effects of all-trans-retinoic acid in APL and STI571 in chronic myeloid leukemia have shown us the direction of cancer therapy in the 21st century. We should shift the paradigm from nonspecific cytotoxic chemotherapy to therapy that specifically targets the genes or gene products that are responsible for leukemogenesis.
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PMID:How high can we increase complete remission rate in adult acute myeloid leukemia? 1118 81

Bcr/abl fusion gene, in experimental models, induces survival to growth factor deprivation and hypersensitivity to IL3. However, conflicting data were reported about chronic myeloid leukemia (CML) progenitors. We investigated the responsiveness of purified CML CFU-GM to GM-CSF/IL3 and their survival to growth factor deprivation. CFU-GM hypersensitivity to IL3 and/or GM-CSF was found in 3/11 CML cases only. CML CFU-GM survived well in stroma-free 'mass' culture (5 x 10(4) cells/ml) without cytokine addition, up to day 11, average recovery being around 95% in medium + 10% fetal bovine serum and 67-81% in serum-free medium. Conversely, normal progenitors declined steadily, particularly after extensive purification (18 +/- 10% recovery at the 7th day), and in serum-free medium (4 +/- 6% recovery). By contrast, normal and CML CFU-GM declined in a similar way in limiting dilution cultures (1-10 cells/50 microl). We also investigated the effects of retinoic acid and alpha-interferon on CFU-GM survival. Both all-trans- and 13-cis retinoic acid, particularly in combination with alpha-interferon, reduced CML CFU-GM recovery down to normal progenitors' values. In conclusion, hypersensitivity to CSFs is rare in CML, whereas resistance to growth factor deprivation has been confirmed in mass, but not in limiting, dilution cultures. Both stereoisomers of retinoic acid, at therapeutic concentrations and in combination with alpha-interferon, can overcome the survival advantage of CML progenitors.
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PMID:Growth advantage of chronic myeloid leukemia CFU-GM in vitro: survival to growth factor deprivation, possibly related to autocrine stimulation, is a more common feature than hypersensitivity to GM-CSF/IL3 and is efficiently counteracted by retinoids +- alpha-interferon. 1123 66

Vasculitis may accompany neoplasias and be of paraneoplastic type or associated with drugs used in patient treatment. We evaluated skin biopsies of twenty-eight cases with vasculitis accompanying leukemias reviewed and clinical outcome was evaluated. Eleven of the 28 cases had paraneoplastic vasculitis and 17 had vasculitis associated with various drugs including chemotherapy, cytokines and antibacterial agents. Paraneoplastic vasculitis was seen in 3 cases with chronic myelocytic leukemia in blastic phase, 5 patients with acute myeloblastic leukemia, and 3 with myelodysplastic syndrome. Drugs responsible for the 17 cases of vasculitis included hydroxyurea, vincristine, cytosine-arabinoside, methotrexate, all-trans retinoic acid, granulocyte-colony stimulating factor, interferon and antibiotics. Paraneoplastic vasculitis is not rare in leukemias and may be a manifestation of the blastic phase of chronic myeloid leukemia. Furthermore paraneoplastic vasculitis can be fatal in myelodysplastic syndromes and may be present clinically before the specific diagnosis is made. Drugs used in routine therapy may be the cause of the vasculitis, thus skin biopsy should be performed in all cutaneous lesions in patients with hemopoietic neoplasias.
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PMID:Vasculitis and leukemia. 1142 10

The accuracy of cytogenetic diagnosis in the management of hematological malignancies has improved significantly over the past 10 years. Fluorescence in situ hybridization (FISH), a technique of molecular cytogenetics, has played a pivotal role in the detection of unique sub-microscopic chromosomal rearrangements that helped in the identification of chromosomal loci, which contain genes involved in leukemogenesis. We studied the feasibility and sensitivity of the FISH technique for molecular analysis of translocations markers, t(9;22) and t(15;17) for accurate molecular diagnosis and for monitoring the disease in 21 patients with chronic myeloid leukemia (CML) who received interferon-alpha and/or chemotherapy (7 patients), bone marrow transplantation (14 patients), and 14 patients with acute promyelocytic leukemia (APL) who received all-trans-retinoic acid (ATRA) and/or chemotherapy. We also applied conventional karyotyping (CK) for identification of t(9;22) and t(15;17) at diagnosis. All CML cases had a Ph; t(9;22) and except for two cases all APL had t(15;17). The FISH studies on CML marrows in complete cytogenetic remission (CCR) (100% Ph- by CK) achieved by IFN-alpha, showed 0-2.5% of cells with BCR-ABL fusion in first cytogenetic remission (Controls, range 0.5-1.5%). Repeat follow-up FISH studies could be done in two cases in remission, which demonstrated 0-10% of cells with BCR-ABL fusion. Evaluation of Ph positive status of CML marrow at diagnosis by CK (100% Ph+ cells) and FISH (80-92% BCR-ABL fusion) pointed the existence of dormant clone of normal residual hematopoietic cells along with actively proliferating clones of Ph positive cells. Fluorescence in situ hybridization analysis of post-BMT CML marrows in CCR (0% Ph+ mitoses) could detect MRD with range of 1-6%. Among 14 patients, 9 who showed percentage of BCR-ABL positive cells (0.0-1.5%) almost similar to normal controls, 6 patients had comparatively good prognosis (disease-free survival 7-14 months). Of five patients with residual leukemic cells in the range of 2-6%, 4 relapsed within a period of 3-24 months. Fourteen APL patients in CCR [100% t(15;17) negative cells by CK] were evaluated by FISH to check the presence of residual leukemic cells. In these patients FISH could efficiently detect 1-14.5% of residual cells with PML-RARA (patients mean MRD 5%, controls mean MRD 3.5%, P=.02). Since the time of FISH analysis, 5 to 7 patients with higher fraction of leukemic cells (5-11%) relapsed within a short period (1-7 months). On the contrary, 5 of 7 patients with either absence or low percentage of PML-RARA positive cells remained in complete remission for 11-24 months. Our data show that FISH has a potential to detect and measure the fraction of aberrant malignant cells in remission marrows, induced by BMT in CML and chemotherapy in APL. These findings encourage the investigations on a large scale to merit its potential for identification of patients at high risk. In the present studies, FISH on interphase cells also demonstrated its efficiency in the molecular diagnosis by its ability to detect BCR-ABL and PML-RARA fusion in CML with masked/variant Ph and t(15;17) negative APL, respectively. The efficiency of technique in molecular diagnosis was also proved in one of the CML patients who progressed to myeloid blastic phase where interphase FISH could identify an extra BCR-ABL fusion on both chromosomes 9 indicating insertion of BCR into ABL and its duplication.
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PMID:Fluorescence in situ hybridization: a highly efficient technique of molecular diagnosis and predication for disease course in patients with myeloid leukemias. 1175 52

Combination of STI571, a tyrosine kinase inhibitor, with other drugs may be beneficial in the treatment of chronic myeloid leukaemia (CML). We measured the effects of STI571, AG490, farnesyltransferase inhibitor (FTI), interferon alpha (IFN-alpha), cytosine arabinoside (Ara-C) and all-trans retinoic acid (ATRA), singly and in combination, on clonogenic leukaemic cell proliferation. STI571, IFN-alpha and ATRA each reduced proliferation by 50-60%; AG490, FTI and Ara-C had less effect. Comparing the observed and expected (i.e. additive) effects of drug combinations showed STI571 + FTI, STI571 + AG490 and IFN-alpha + ATRA were additive; STI571 + IFN-alpha, IFN-alpha + Ara-C and STI571 + AG490 + FTI were less than additive. Thus, STI571 + FTI, STI571 + AG490 and IFN-alpha + ATRA may be better combination therapies for CML than STI571 + IFN-alpha, IFN-alpha + Ara-C or STI571 + AG490 + FTI.
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PMID:Effects of combinations of therapeutic agents on the proliferation of progenitor cells in chronic myeloid leukaemia. 1184 11

Loss of the inhibition of apoptosis is important in leukemogenesis and may influence the prognosis. Survivin is an inhibitor of apoptosis that shows selective expression during fetal development and in human malignancies. Survivin expression was examined in human leukemias using the reverse transcriptase-polymerase chain reaction. Survivin gene expression was detected in 17 of 31 patients with acute myelocytic leukemia and 11 of 16 patients with acute lymphocytic leukemia but was not identified in normal bone marrow cells. Survivin expression was lower in patients with M3 acute myelocytic leukemia than in patients with other types of acute leukemia. Survivin was not detected in the chronic phase of chronic myelocytic leukemia but was observed in 5 of 7 patients with chronic myelocytic leukemia in blastic crisis. These findings suggest a relationship between survivin gene expression and hematopoietic cell differentiation. In fact, survivin gene expression was down-regulated during the differentiation of HL-60 cells after treatment with dimethyl sulfoxide or all-trans-retinoic acid. Moreover, the disease-free survival rates of patients with survivin expression were lower than in patients without survivin expression. Accordingly, survivin may have a role in leukemogenesis as well as in other malignancies. Detecting survivin may also provide prognostic information.
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PMID:Expression of the antiapoptosis gene survivin in human leukemia. 1193 62

Arsenic trioxide (As(2)O(3)) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) as well as in patients with APL in whom all-trans-retinoic acid and conventional chemotherapy failed. Chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs. To determine if As(2)O(3) might be useful for the treatment of chronic myelogenous leukemia, we examined the ability of As(2)O(3) to induce apoptosis in K562 cells. In vitro cytotoxicity of As(2)O(3) was evaluated in K562 cells by a MTT assay; the IC(50) value for As(2)O(3) was determined to be 10 microM. When analyzed by agarose gel electrophoresis, the DNA fragments became evident after incubation of the cells with 20 microM As(2)O(3) for 24 h. We also found morphological changes and chromatin condensation of the cells undergoing apoptosis. Activation of caspase-3 was observed 6 h after treatment with 20 microM As(2)O(3) by a Western blot analysis. Next, we examined the MAP kinase-signaling pathway of As(2)O(3)-induced apoptosis in K562 cells. As(2)O(3) at 10 microM strongly induced the activation of p38 and JNK 1/2, while ERK 1/2 was inhibited. In addition, pretreatment of SB203580, a specific inhibitor of p38, inhibited As(2)O(3) induced apoptotic cell death. These results suggest that As(2)O(3) is able to induce the apoptotic activity in K562 cells, and its apoptotic mechanism may be associated with the activation of p38.
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PMID:Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase. 1229 96

Chronic myelogenous leukemia (CML) is a slowly progressive disease characterized by the overproduction of granulocytes (neutrophils, eosinophils, and basophils). A blood smear shows moderate elevations in white blood cell counts that may persist for years and be benign. Platelets are increased in number, although their function is impaired, resulting in symptoms of easy bleeding (purpura, swollen gums). Conventional medical treatment is a marrow transplant and alkylating agents, which are usually prescribed only during crisis. Several nutrients and botanicals have been studied for use in CML, including vitamin A and all-trans retinoic acid (Retin-A), vitamin D3, vitamin E, vitamin B12, indirubin (found in herbs including Indigofera tinctoria and Isatis tinctoria), and Curcuma longa. This article briefly reviews the scientific literature on the therapeutic use of these nutrients for CML.
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PMID:Nutritional support for chronic myelogenous and other leukemias: a review of the scientific literature. 1241 Jun 24

Hematological malignancies including acute leukemia, and multiple myeloma are disorders characterized by the accumulation of neoplastic hematopoietic cells, resulting in aggressive clinical manifestations with poor prognosis. The therapeutic approach to these disorders is basically chemotherapy for achieving complete remission based on the concept of total cell kill. However, severe side effects and complications such as serious infection and bleeding due to anti-cancer drugs are major problems in the clinical setting. In addition, repeated episodes of relapse of the disease may lead to refractory or chemotherapy-resistant disorders. These problems are occurred because anti-cancer agents have effects on both cancer cells and normal hematopoietic cells. The clinical evidences thus suggest the limitations of the chemotherapy for hematological malignancies: novel effective therapeutic approaches with less toxicity are therefore actively being sought. Differentiation-inducing therapy employing a physiologically active derivative of vitamin A, all-trans retinoic acid (ATRA), brought remarkably advances in the therapeutic outcome of APL at the end of last century. More recently, the clinical success of imatinib mesylate (STI571), potent competitive inhibitor of the Bcr/Abl protein tyrosine kinase, in the treatment of CML has focused enthusiasm toward molecular targeted therapy for the hematological malignancies. The therapeutic activity of these agents can be explained by their abilities to modify cellular growth, differentiation, and apoptosis in cells by activating unknown gene programs that molecular cellular proliferation. We have actively sought out new agents among natural products and cytokines with the ability to induce cellular differentiation and apoptosis. In this symposium, I will present our recent data of these novel compounds and their molecular mechanisms for inducing differentiation and apoptosis of hematological malignant cells.
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PMID:A novel therapeutic approach for hematological malignancies based on cellular differentiation and apoptosis. 1243 Aug 59

Significant advances have been made in the development of targeted interventions for hematologic malignancies. Progress has been made in defining the molecular pathogenesis of human leukemias. Data indicate that nonrandom, somatically acquired translocations, inversions, and other abnormalities occur in many acute leukemias. In the treatment of acute promyelocytic leukemia (APL), targeted therapy with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy leads to dramatic improvements in disease-free survival. Imatinib mesylate, a signal transduction inhibitor that inhibits tyrosine kinase activity, the protein product of the ABL proto-oncogene, has remarkable activity in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). Farnesyltransferase inhibitors (FTIs), a promising class of agents that target multiple pathways including Ras proteins, are potential anticancer therapy for a wide range of malignancies, including leukemias and myelodysplastic syndromes (MDS). There also is evidence that recombinant human erythropoietin therapy (r-HuEPO) can benefit patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. This supplement will discuss advances in our understanding of human leukemias, including the use of unconjugated monoclonal antibodies such as Campath-1H (Wellcome, Beckenham, UK, and Ilex Oncology, San Antonio, TX) and rituximab and immunoconjugates such as gemtuzumab ozogamicin and BL-22. Although these novel therapies are beginning to fulfill their promise, continued research efforts are needed to determine the optimal role of targeted therapy in acute and chronic leukemias.
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PMID:Advancing the treatment of hematologic malignancies through the development of targeted interventions. 1244 45


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