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)

Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancer. The molecular pathogenesis of chronic myelogenous leukemia (CML) in particular, depends on formation of the bcr-abl oncogene, leading to constitutive expression of the tyrosine kinase fusion protein, Bcr-Abl. Based on these observations, imatinib was developed as a specific inhibitor for the Bcr-Abl protein tyrosine kinase. The expanding understanding of the basis of imatinib-mediated tyrosine kinase inhibition has revealed a spectrum of potential new antitumor applications beyond the powerful activity already reported in the treatment of CML. Imatinib has shown activity in vivo against PDGF-driven tumor models including glioblastoma, dermatofibrosarcoma protuberans and chronic myelomonocytic leukemia. Antiangiogenic effects have been demonstrated by inhibition of PDGF-, VEGF (vascular endothelial growth factor)- and bFGF- (basic fibroblast growth factor) induced angiogenesis in vivo, and by inhibition of angiogenesis and tumor growth in an experimental bone metastasis model. Imatinib has been shown to reduce interstitial fluid pressure in an experimental colonic carcinoma model by blocking PDGF-mediated effects on tumor-associated blood vessels and stromal tissue. It is also a potent inhibitor of the Kit receptor tyrosine kinase, and has demonstrated activity clinically against the Kit-driven gastrointestinal stromal tumor (GIST) and experimentally in small-cell lung cancer cell lines. The pharmacology of imatinib and its activity in various tumor models is discussed.
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PMID:Pharmacology of imatinib (STI571). 1252 70

Most of the signal transduction pathways are mediated by protein kinases regulating every aspect of cell function. Mutations which deregulate their expression or their function or both result in cancers. Therefore, protein kinase inhibitors has become the focus of development of new therapies for cancer. Almost all 120 protein tyrosine kinases are involved in signaling, whereas only a handful of Ser/Thr kinases are involved. Thus, most of the effort is directed toward the development of tyrosine phosphorylation inhibitors. The success of Gleevec in the treatment of chronic myeloid leukemia and of Iressa for lung cancer validates the approach.
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PMID:Protein kinase inhibitors as a therapeutic modality. 1280 33

The synthesis and biological evaluation of a homologous series of conjugates (9-13) of 2,5-diaziridinylbenzoquinone (DZQ) and 9-carbonylacridine, a DNA intercalating moiety, via a polymethylene unit (n=2-6) are described. In addition, the non-acridine compound 14, analogous to compound 12, and the 5-methyl-DZQ derivatized conjugate 15, an analog of compound 10, were also prepared. Through a Comet assay, compounds 9-13 were shown to produce DNA interstrand cross-links at submicromolar concentrations, consistent with K562 leukemia cells accumulating in the G2/M stage in the cell cycle. The cytotoxicity of compounds 9-15 was examined using a MTT assay on several human cancer cell lines, including chronic myeloid leukemia K562, the non-small cell lung cancers H596 and H460, and colon carcinoma cells BE and HT29. H460 and HT29 are rich in DT-diaphorase (DTD), and H596 and BE cells have negligible amounts of functional DTD. Under continuous exposure of drugs, except to the non-aziridine compound 19b, the IC50 values of all other compounds were determined to be in the range of 0.3-11.3 nM. Compound 10, which has a propyl linker group, was subjected to in vivo studies. When BDF1 mice with established mouse mammary carcinoma were treated with compound 10 (2 mg/kg at day 1 and 5 mg/kg at day 7), a significant delay (9-10 days) in cancer growth was recorded when compared to untreated controls. Furthermore, administration of compound 10 to nu/nu BDF1 mice bearing human lung cancer H460 xenograft (1.5 mg/kg for 10 for five consecutive days from day 13 and 17) also showed a significant reduction in tumor growth compared to untreated controls. The half-life of compound 10 in the presence of five different peptidases (porcine esterase, carboxypeptidase A, B and Y, and pepsin) was determined to be between 30 and 60 h.
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PMID:Synthesis and biological evaluation of novel diaziridinylquinone-acridine conjugates. 1450 82

Non-Hodgkin's lymphoma (NHL) occurring as a synchronous malignancy with chronic myelogenous leukemia (CML) is rare. To our knowledge, this is the first case reported of a patient who developed mantle cell lymphoma (MCL) after therapy with imatinib mesylate for CML. After a 3-year history of CML, the patient developed a lymphocytosis associated with diarrhea, anorexia, and weight loss. Imaging studies revealed abdominal adenopathy and extensive lymphomatous infiltration of the liver, stomach, pancreas, and kidneys. Flow cytometric and cytogenetic studies were consistent with MCL. Fluorescence in situ hybridization (FISH) of the bone marrow revealed a genetically distinct lymphoid neoplasm rather than an extramedullary blast crisis of CML. The development of lung cancer, prostate cancer, CML and MCL in this patient suggests a genetic predisposition, although other factors, including environmental exposures and therapy with imatinib mesylate could have had a contributory or synergistic role in the development of MCL.
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PMID:Blastic mantle cell lymphoma developing concurrently in a patient with chronic myelogenous leukemia and a review of the literature. 1505 16

This 2002 European Group for Blood and Marrow Transplantation (EBMT) activity survey concentrates on current status, increase and decrease in haematopoietic stem cell transplantation (HSCT) activity in Europe and investigates the association of transplant rates with team density. In 2002, there were 20 207 HSCT, 6915 allogeneic (34%), 13 292 autologous (66%) and 3947 additional re- or multiple transplants collected from 586 centres in 39 European countries. Main indications were leukaemias (6523 (32%; 76% allogeneic)); lymphomas (10 760 (53%; 92% autologous)); solid tumours (1913 (9%; 92% autologous)) and nonmalignant disorders (874 (4%; 92% allogeneic)). Compared to 2001, there were increases (>10%) for AML, ALL 1st CR, CML not 1st cP, MDS, SAA and CLL in allogeneic HSCT and for MDS, Ewing's sarcoma, soft-tissue sarcoma and ovarian cancer in autologous HSCT. Decreases (>10%) were observed in autologous HSCT for acute leukaemias beyond 1st CR, CML cP, glioma, breast cancer and lung cancer. Correlation of transplant rates (number of transplants per 10 million inhabitants) with team density (number of transplant teams per 10 million inhabitants) suggests different diffusion patterns for autologous compared to allogeneic HSCT. These data describe current practice for blood and marrow transplantation in Europe and give some hints about mechanisms involved in HSCT rates.
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PMID:Haematopoietic stem cell transplantation (HSCT) in Europe 2002. Changes in indication and impact of team density. A report of the EBMT activity survey. 1551 6

BAY 43-9006, a multikinase inhibitor that targets Raf, prevents tumor cell proliferation in vitro and inhibits diverse human tumor xenografts in vivo. The mechanism of action of BAY 43-9006 remains incompletely defined. In the present study, the effects of BAY 43-9006 on the antiapoptotic Bcl-2 family member Mcl-1 were examined. Treatment of A549 lung cancer cells with BAY 43-9006 diminished Mcl-1 levels in a time- and dose-dependent manner without affecting other Bcl-2 family members. Similar BAY 43-9006-induced Mcl-1 downregulation was observed in ACHN (renal cell), HT-29 (colon), MDA-MB-231 (breast), KMCH (cholangiocarcinoma), Jurkat (acute T-cell leukemia), K562 (chronic myelogenous leukemia) and MEC-2 (chronic lymphocytic leukemia) cells. Mcl-1 mRNA levels did not change in BAY 43-9006-treated cells. Instead, BAY 43-9006 enhanced proteasome-mediated Mcl-1 degradation. This Mcl-1 downregulation was followed by mitochondrial cytochrome c release and caspase activation as well as enhanced sensitivity to other proapoptotic agents. The caspase inhibitor Boc-D-fmk inhibited BAY 43-9006-induced caspase activation but not cytochrome c release. In contrast, Mcl-1 overexpression inhibited cytochrome c release and other features of BAY 43-9006-induced apoptosis. Conversely, Mcl-1 downregulation by short hairpin RNA enhanced BAY 43-9006-induced apoptosis. Collectively, these findings demonstrate that drug-induced Mcl-1 downregulation contributes to the proapoptotic effects of BAY 43-9006.
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PMID:The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. 1600 48

The bovine leukemia virus (BLV) is the causative agent of enzootic bovine leucosis. This study investigated the presence of the BLV in leukemia (179 acute lymphoblastic leukemia, 292 acute myeloid leukemia and 46 chronic myelogenous leukemia cases) and 162 lung cancer patients (139 adenocarcinoma, 23 squamous cell carcinoma) to determine if the BLV is a causative organism of leukemia and lung cancer in Koreans. A BLV infection was confirmed in human cells by PCR using a BLV-8 primer combination. All 517 cases of human leukemia and 162 lung cancer were negative for a PCR of the BLV proviral DNA. In conclusion, although meat has been imported from BLV endemic areas, the BLV infection does not appear to be the cause of human leukemia or lung cancer in Koreans. These results can be used as a control for further studies on the BLV in Koreans.
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PMID:Investigation of the bovine leukemia virus proviral DNA in human leukemias and lung cancers in Korea. 1610 Apr 51

There is an increasing evidence supporting the cancer stem cell hypothesis. Normal stem cells in the adult organism are responsible for tissue renewal and repair of aged or damaged tissue. A substantial characteristic of stem cells is their ability for self-renewal without loss of proliferation capacity with each cell division. The stem cells are immortal, and rather resistant to action of drugs. They are able to differentiate and form specific types of tissue due to the influence of microenvironmental and some other factors. Stem cells divide asymmetrically producing two daughter cells -- one is a new stem cell and the second is progenitor cell, which has the ability for differentiation and proliferation, but not the capability for self-renewal. Cancer stem cells are in many aspects similar to the stem cells. It has been proven that tumor cells are heterogeneous comprising rare tumor initiating cells and abundant non-tumor initiating cells. Tumor initiating cells -- cancer stem cells have the ability of self-renewal and proliferation, are resistant to drugs, and express typical markers of stem cells. It is not clear whether cancer stem cells originate from normal stem cells in consequence of genetic and epigenetic changes and/or by redifferentiation from somatic tumor cells to the stem-like cells. Probably both mechanisms are involved in the origin of cancer stem cells. Dysregulation of stem cell self-renewal is a likely requirement for the development of cancer. Isolation and identification of cancer stem cells in human tumors and in tumor cell lines has been successful. To date, the existence of cancer stem cells has been proven in acute and chronic myeloid leukemia, in breast cancer, in brain tumors, in lung cancer and gastrointestinal tumors. Cancer stem cell model is also consistent with some clinical observations. Although standard chemotherapy kills most cells in a tumor, cancer stem cells remain viable. Despite the small number of such cells, they might be the cause of tumor recurrence, sometimes many years after the "successful" treatment of primary tumor. Growth of metastases in distinct areas of body and their cellular heterogeneity might be consequence of cancer stem cell differentiation and/or dedifferentiation and asymmetric division of cancer stem cells. Further characterization of cancer stem cells is needed in order to find ways to destroy them, which might contribute significantly to the therapeutic management of malignant tumors.
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PMID:Cancer stem cells. 1628 86

A nationwide survey of hematopoietic cell transplantation (HCT) was started in Japan in 1991, and the analyzed survey data have been presented as the annual report of the Japan Society for Hematopoietic Cell Transplantation. The 10-year overall survival (OS) rates after HCT for each disease are as follows: acute myelogenous leukemia, 44.2%; acute lymphocytic leukemia, 33.7%; adult T-cell leukemia, 24.6%; chronic myelogenous leukemia, 53.3%; myelodysplastic syndrome, 37.3%; non-Hodgkin's lymphoma, 41.5%; Hodgkin's lymphoma, 50.8%; aplastic anemia, 72.5%; breast cancer, 37.1%; germ cell tumor, 52.6%; and ovarian cancer, 44.2%. The 5-year OS rates for multiple myeloma and lung cancer were 40.6% and 23.6%, respectively. Except in cord blood transplantation, engraftment was accomplished in more than 90% of patients. The respective frequencies of acute graft-versus-host disease (GVHD) and chronic GVHD were 41.1% and 34.9% for related bone marrow transplantation (BMT), 66.8% and 34.5% for unrelated BMT, 52.9% and 36.0% for allogeneic peripheral blood stem cell transplantation, and 53.3% and 32.1% for allogeneic cord blood transplantation. OS for each disease was analyzed by patient age, stem cell source, donor type, disease status, and disease type. These data provide objective and valuable information for hematologists as well as for patients who need HCT.
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PMID:Current status of hematopoietic cell transplantation for adult patients with hematologic diseases and solid tumors in Japan. 1651 37

Inhibition of oncogenic protein kinases by small compound inhibitors has proven to be a valuable strategy for the directed and target-specific treatment of an ever-increasing number of cancer types. These include the treatment of chronic myeloid leukemia with the Bcr-Abl inhibitor imatinib and non-small-cell lung cancer with the epidermal growth factor inhibitors erlotinib and gefitinib. Unfortunately, initially successful therapy is often hampered by relatively rapid onset of resistance to the drug and subsequent relapse, particularly in patients with advanced disease. In the majority of cases this is caused by expansion of clones containing mutated forms of the targeted kinases, which confer insensitivity to the drug of the cancer cell. In addition, multiple factors including pharmacokinetic issues such as suboptimal drug delivery further contribute to resistance formation. Loss of target dependence due to the activation of parallel signaling pathways has also been reported as cause for acquired drug insensitivity. Here, we discuss currently applied as well as potential future strategies that can be applied to overcome and avoid resistance to drug therapy.
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PMID:Strategies to overcome resistance to targeted protein kinase inhibitors in the treatment of cancer. 1654 54


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