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)

The molecular cloning of the t(5;10)(q33;q22) associated with atypical chronic myeloid leukemia (CML) is reported. Fluorescence in situ hybridization (FISH), Southern blot, and reverse transcriptase- polymerase chain reaction analysis demonstrated that the translocation resulted in an H4/platelet-derived growth factor receptor betaR (PDGFbetaR) fusion transcript that incorporated 5' sequences from H4 fused in frame to 3' PDGFbetaR sequences encoding the transmembrane, WW-like, and tyrosine kinase domains. FISH combined with immunophenotype analysis showed that t(5;10)(q33;q22) was present in CD13(+) and CD14(+) cells but was not observed in CD3(+) or CD19(+) cells. H4 has previously been implicated in pathogenesis of papillary thyroid carcinoma as a fusion partner of RET. The H4/RET fusion incorporates 101 amino acids of H4, predicted to encode a leucine zipper dimerization domain, whereas the H4/PDGFbetaR fusion incorporated an additional 267 amino acids of H4. Retroviral transduction of H4/PDGFbetaR, but not a kinase-inactive mutant, conferred factor-independent growth to Ba/F3 cells and caused a T-cell lymphoblastic lymphoma in a murine bone marrow transplantation assay of transformation. Mutational analysis showed that the amino-terminal H4 leucine zipper domain (amino acids 55-93), as well as H4 amino acids 101 to 386, was required for efficient induction of factor-independent growth of Ba/F3 cells. Tryptophan-to-alanine substitutions in the PDGFbetaR WW-like domain at positions 566/593, or tyrosine-to-phenylalanine substitutions at PDGFbetaR positions 579/581 impaired factor-independent growth of Ba/F3 cells. H4/PDGFbetaR is an oncoprotein expressed in t(5;10)(q33;q22) atypical CML and requires dimerization motifs in the H4 moiety, as well as residues implicated in signal transduction by PDGFbetaR, for efficient induction of factor-independent growth of Ba/F3 cells. (Blood. 2001;97:3910-3918)
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PMID:H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22). 1138 34

Recombinant factor VIIa (rFVIIa, NovoSeven) is effective and appears safe in the management of bleeding episodes and provision of surgical cover in haemophilia patients with inhibitors. Additionally, rFVIIa has been considered as a universal haemostatic agent, prompting its use in the management of severe uncontrolled surgical bleeding in patients without pre-existing coagulopathies. Recombinant FVIIa has been used in 5 patients (aged 2.5 to 73.0 years; median 48 years) with uncontrolled bleeding during or after open-heart surgery. Satisfactory haemostasis was achieved with a single dose or rFVIIa 30 microg/kg, that resulted in reduction of blood loss from a mean of 4,170 ml (650-8,000 ml) to 262.5 ml (220-334 ml). No significant adverse events were reported. Recombinant FVIIa was also successfully used in controlling post-surgical bleeding in two patients with Crohn's disease, one patient with bleeding duodenal ulcer and another with false thoracic aneurysm. It was also effective in controlling bleeding post-splenectomy in a patient with chronic myeloid leukaemia, and following anterior exenteration in a patient with cervical carcinoma. A randomised study comparing the efficacy of a single perioperative dose of rFVIIa with placebo in patients undergoing transabdominal prostatectomy was conducted by Levi and colleagues [6]. An interim analysis showed a significant reduction in mean blood loss from 2,450 +/- 350 ml to 1,400 +/- 190 ml between placebo and rFVIIa groups respectively (p = 0.007). Among trauma patients, Kenet et al. reported success in treating uncontrolled bleeding from a gun-shot wound to the inferior vena cava, using two doses of rFVIIa 60 microg/kg [7]. This treatment has subsequently been used in 6 surgical patients with uncontrolled bleeding and in 7 cases of traumatic bleeding, with remarkable results. In conclusion, rFVIIa appears to be effective and safe in the management of uncontrolled surgical and traumatic haemorrhage in patients not known to have inherited coagulopathy.
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PMID:The use of recombinant factor VIIa in controlling surgical bleeding in non-haemophiliac patients. 1221 47

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

HEX1/hExo1 is a Class III nuclease of the RAD2 family with 5' to 3' exonuclease and flap structure-specific endonuclease activities. HEX1/hExo1 is expressed at low levels in a wide variety of tissues, but at higher levels in fetal liver and adult bone marrow, suggesting HEX1/hExo1 is important for hematopoietic stem cell development. A putative HEX1/hExo1 promoter fragment extending from -6240 to +1600bp exhibits cell-type specific activity in transient transfection assays. This fragment directs high luciferase reporter gene expression in the hematopoietic cell line K562, chronic myelogenous leukemia cells, but low luciferase expression in the non-hematopoietic cell line HeLa, human cervical carcinoma cells. Deletion studies identified a fragment spanning -688 to +1600bp that exhibits full transcriptional activity while a slightly shorter fragment from -658 to +1600bp exhibits significantly decreased promoter activity. In vitro binding assays revealed DNA-binding activities that interact with -687 to -681bp and -665 to -658bp elements. Oligonucleotide competition and antibody disruption studies determined that the transcription factor CREB-1 recognizes the -687 to -681bp element, while transcription factors Sp1 and Sp3 recognize the -665 to -658bp element. Mutation of either the CREB-1 or Sp1/Sp3 binding sites dramatically reduces HEX1/hExo1 promoter activity and elimination of both elements abolishes promoter activity.
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PMID:Identification of the human HEX1/hExo1 gene promoter and characterization of elements responsible for promoter activity. 1253 89

The multiple tumor syndrome is an unusual pathologic condition, which consists in association of multiple malignancies in the same patient. Seven cases are discussed: two women, five men, aged 32-70 years. The period between the two neoplasias was 2-23 years (in 6 cases). In one case the two malignancies appeared concomitantly. The hematological malignancies were: multiple myeloma: 2 cases; chronic granulocytic leukemia: 2 cases; chronic lymphatic leukemia: 3 cases. In four cases, the solid tumor followed the hematological malignancy at variable periods (2 and 4 years). In other two cases, the solid tumors preceded the hematological malignancy with 2 years, 23 years respectively. The solid tumors were genital cancers, malignant melanoma, spino-cellular carcinoma, thyroid cancer, hemangiosarcoma. In a single case the second tumor was a hematological malignancy too (NHL-diffuse lymphocytic lymphoma). Possible implications of previous therapy and environmental factors are discussed.
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PMID:The multiple tumor syndrome. Personal experience. 1263 87

To design a specific immunotherapy for leukemia patients, the identification of leukemia-associated antigens (LAAs) is a pivotal step. Antileukemic effects after hematopoetic stem cell transplantation for myeloid leukemias are observed and might be related to the recognition of LAAs. Using the serological screening of an expression library (SEREX) of K562 cells, we identified 16 different clones encoding LAAs eliciting a humoral immune response, among them the heat shock proteins HSJ2 and HSP70, the M-phase phosphoprotein 11 (MPP11), the BRCA1-associated protein (BRAP), the Jkappa recombination binding protein (RBPJkappa) and the receptor for hyaluronic acid mediated motility (RHAMM). Serological responses to MPP11 were observed in 7/19 (37%) of patients with acute myeloid leukemia (AML) and 6/16 (38%) of patients with chronic myeloid leukemia (CML), but not in healthy volunteers (0/20). IgG antibodies directed against MPP11 were also detected in 25-50% of the sera of patients with solid tumors such as melanoma, renal cell, ovarian and breast carcinoma. mRNA expression of MPP11 was detected in 20/20 AML patients and 7/10 patients with CML. In normal tissues, strong mRNA expression of MPP11 was only detected in testis. By real-time PCR, we detected upregulation of MPP11 in leukemic blasts. Simultaneous humoral immune responses to 2 or more of the 16 LAAs identified here was observed, suggesting the feasibility of a polyvalent vaccination as an option for immunotherapies in leukemia patients.
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PMID:Characterization of several leukemia-associated antigens inducing humoral immune responses in acute and chronic myeloid leukemia. 1280 Jan 98

Anthracycline cardiotoxicity can induce dilated cardiomyopathy (DCM). Nine patients (four men) experienced postchemotherapy DCM: age at time of tumour diagnosis ranged from 1-45 years (mean 13.5 +/- 19 years); interval time between tumour and HT was 3-23 years (mean 10.8 +/- 6.6) and age at HT ranged from 10-65 years (30.8 +/- 20.1). Interval between end of chemotherapy and beginning of cardiac symptoms was 5.71 +/- 4.6 years. Mean age at DCM diagnosis was 19.2 +/- 19.7 (range 1-50 years). Interval between start of chemotherapy and DCM ranged from 1 month to 10 years (mean 3.15 +/- 3.6 years). Tumours were Ewing sarcoma (7-year-old boy), paratesticular rabdomyosarcoma (1-year-old boy), Wilms tumor with pulmonary metastasis (3-year-old girl), bilateral breast carcinoma (45-year-old woman), uterine leiomyosarcoma (44-year-old woman), acute myelocytic leukemia (1.5-year-old boy and 17-year-old girl), and chronic myelocytic leukemia (5-year-old boy). All patients had high pulmonary resistance values. One patient with chronic myelocytic leukemia (14 year-old at HT) died due to graft failure on the first postoperative day. At follow-up (mean, 80.4 +/- 69.3 months) two patients died: a 32-year-old woman (acute myelocytic leukemia) 1 year after HT for sepsis and a 68-year-old woman who had breast adenocarcinoma recurrence 81 months after HT. The remaining patients are alive, in good condition with no difference in survival from other transplanted patients (P =.757). Patients with end-stage postchemotherapy DCM without evidence of tumour recurrence can safely undergo HT.
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PMID:Heart transplantation in chemotherapeutic dilated cardiomyopathy. 1282 9

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

A number of agents targeting components of pathways and processes critical to neoplastic transformation and progression are ongoing clinical development. Notable successes include imatinib mesylate (STI571, Gleevec) in Chronic Myelogenous Leukemia (CML), and Gastrointestinal Stromal Tumors (GIST) and trastuzumab (Herceptin) in HER2 amplified breast carcinoma. More recently, gefitinib (ZD1839, Iressa) and bortezomib (PS-341, Velcade) have been approved for refractory nonsmall cell lung carcinoma (NSCLC) and multiple myeloma (MM), respectively. In addition, promising results from randomized studies of bevacizumab (Avastin) and cetuximab (IMC-225, Erbitux) have been reported and shortly may lead to their approval for the treatment of colorectal carcinoma (CRC). To what degree the success or failure of these agents has been due to target, the agent, the dose or the selection of patients is uncertain. Certainly, further evaluation of these factors is required to optimize the therapeutic impact of targeted agents and imaging modalities may play a vital role in this process. The purpose of this review is to summarize recent results from trials of selected targeted agents and to suggest roles imaging may play in the further development of these and other targeted agents.
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PMID:Recent advances of molecular targeted agents: opportunities for imaging. 1468 62

Second malignant neoplasms are gradually becoming a recognized long-term complication of successful cancer treatment, and they usually respond poorly to conventional therapy and have an unfavorable outcome. Chronic myeloid leukemia (CML) is a clonal panmyelopathy, rarely seen in children with a specific cytogenetic aberration-the Philadelphia chromosome. The translocation generates an aberrant tyrosine kinase, which drives the malignant process in CML and which is also the molecular target for successful treatment of CML with imatinib. It is also exceedingly rare as a secondary malignant neoplasm in both adults and children. We report two cases of secondary CML. The first occurred after successful treatment for nasopharyngeal carcinoma in a child, and the second after treatment for lymphoma in an adolescent. Both patients had an excellent response to treatment with imatinib and attained complete cytogenetic remissions. We conclude that secondary CML may respond favorably to treatment with imatinib.
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PMID:Favorable early response of secondary chronic myeloid leukemia to imatinib. 1505 13


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