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 potential clinical applications of the prototype first-in-class Hsp90 inhibitor 17AAG and other emerging Hsp90 drugs are very exciting. Rigorously planned and executed clinical trials, incorporating measurement of appropriate biomarkers and pharmocodynamic endpoints are critical for selecting the optimal dose and schedule. A detailed understanding of the molecular mode of action of Hsp90 inhibitors alongside the elucidation of the molecular pathology of individual cancers will help us to identify tumour types and individual patients that will benefit most from treatment. Careful in vitro and in vivo experiments are needed to choose the most potentially advantageous combination studies. It is important to construct a pharmacologic audit trail linking molecular biomarkers and pharmacokinetic and pharmacodynamic parameters to tumour response endpoints. Phase I clinical studies with 17AAG have shown that the drug can be given at does that are well tolerated and that also achieve active pharmacokinetic exposures and elicit molecular signatures of gene and protein expression that are indicative of Hsp90 inhibition. Furthermore, examples of disease stabilisation have been documented, consistent with the generally cytostatic responses that are seen in animal models. Selecting tumour types for Phase II clinical trials must involve balancing 1) our knowledge of molecular response determinants, such as the expression of and dependence upon key client proteins and 2) more pragmatic evidence of antitumour activity in the relevant preclinical models. Examples of likely disease targets include chronic myeloid leukaemia, melanoma, breast, ovarian, brain, thyroid, colorectal and prostate cancer.
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PMID:The clinical applications of heat shock protein inhibitors in cancer - present and future. 1452 90

The regulation of apoptosis is an important potential target for anticancer therapy. The mitochondrial Bcl-2 protein inhibits apoptosis and is therefore an important mediator of resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy and monoclonal antibody therapy. Oblimersen (Genasense, Aventis Pharmaceuticals / Genta Inc) is a 18mer antisense-oligonucleotide (ASO), which specifically binds to the first 6 codons of the human bcl-2 mRNA, resulting in degradation and destruction of the mRNA by RNAse H. Subsequently there is a significant decrease of bcl-2 translation. A growing number of preclinical and clinical studies suggests that the combination of cytotoxic therapy with Oblimersen results in synergistic anticancer efficacy in many hematologic and solid tumors. Due to its low toxicity profile, oblimersen is an ideal combination partner with conventional chemotherapy. Three randomized phase-III trials (malignant melanoma, chronic lymphocytic leukemia, multiple myeloma) have recently finished recruitment. The results of these studies will be available by the end of 2003. Based on preclinical data, a lot of nonrandomized phase-II studies on several different tumor types like AML, CML, NHL, prostate cancer and breast cancer are underway. The manipulation of proapoptotic and antiapoptotic factors in favor of proapoptotic factors by inhibition of the bcl-2 protein translation in order to enhance the efficacy of anticancer treatments represents a promising new treatment concept in oncology.
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PMID:[Proapoptotic therapy with oblimersen (bcl-2 antisense oligonucleotide)--review of preclinical and clinical results]. 1471 45

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily exerting cytotoxic activities toward tumor cells. Herein, we demonstrate that therapeutic concentrations of interferon alpha (IFNalpha) stimulate the expression of high levels of TRAIL mRNA and the release of elevated amounts of a soluble bioactive form of TRAIL (sTRAIL) in both human neutrophils and monocytes. Supernatants harvested from IFNalpha-treated neutrophils/monocytes elicited, on TRAIL-sensitive leukemic cell lines, proapoptotic activities that were significantly reduced by either a combination of TRAIL-R1/Fc and TRAIL-R2/Fc chimeras or neutralizing anti-TRAIL, anti-TRAIL-R1, and anti-TRAIL-R2 antibodies, suggesting that they were mediated by released sTRAIL acting on both TRAIL receptors. Since diseases such as chronic myeloid leukemia (CML) and melanoma are effectively treated with IFNalpha,we also demonstrate that CML neutrophils and peripheral blood mononuclear cells (PBMCs) cultured with IFNalpha at therapeutic concentrations retain the capacity of releasing sTRAIL, suggesting that CML leukocytes, in vivo, might represent an important source of sTRAIL. In this regard, we show that sTRAIL serum levels as well as leukocyte-associated TRAIL significantly increase in melanoma patients following IFNalpha administration. Collectively, these findings indicate that sTRAIL released by IFNalpha-activated neutrophils and monocytes contributes not only to the immunoregulatory actions but also to the therapeutic activities of IFNalpha.
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PMID:IFNalpha-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity on leukemic cells. 1472 4

Multiple isoforms (TAG-1, TAG-2a, TAG-2b, and TAG-2c) of a novel cancer/testis antigen gene have been identified and are expressed in 84-88% of melanoma cell lines tested. The tumor antigen (TAG) genes are also expressed in K562, a myelogenous leukemia cell line, and they have homology to two chronic myelogenous leukemia-derived clones and a hepatocellular carcinoma clone in the human expressed sequence tags (EST) database, thus indicating that their expression is not restricted to melanomas. In contrast to the fact that many cancer/testis antigens are poorly immunogenic, the TAG-derived peptide, RLSNRLLLR, is recognized by HLA-A3-restricted, melanoma-specific CTLs that were obtained from a melanoma patient with spontaneous reactivity to the peptide. Unlike most cancer/testis antigen genes which are located on the X chromosome, the TAG genes are located on chromosome 5. The genes have the additional unusual features of being coded for in an open reading frame that is initiated by one of three nonstandard initiation codons, and the sequence coding the RLSNRLLLR peptide crosses an exon-exon boundary. The properties of the TAG antigens indicate that they are excellent vaccine candidates for the treatment of melanoma and perhaps other cancers.
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PMID:Identification of novel and widely expressed cancer/testis gene isoforms that elicit spontaneous cytotoxic T-lymphocyte reactivity to melanoma. 1487 52

CD44, the main cell surface receptor for hyaluronan (HA), is often overexpressed in tumour cells, and its presence has been related to cell proliferation and migration. Many of the functions of CD44 are mediated through its interaction with hyaluronan. This study investigated the expression of CD44 in CML-1 and CML-10c2 canine melanoma cell lines and melanoma biopsies, and the production of hyaluronan and versican by the canine melanoma cell lines. Versican is an extracellular proteoglycan that binds hyaluronan, forming a tridimensional pericellular coat surrounding the cells. Both canine melanoma cell lines expressed CD44 and produced HA, but only CML-1 produced versican. Cells expressing all three components (CD44, HA and versican) formed abundant extracellular matrices as demonstrated by a particle exclusion assay. CD44 was present within benign and malignant melanomas, but its expression was more intense in malignant melanomas (P < 0.01). In high CD44-expressing tumours, CD44 tended to be present in the periphery of malignant melanomas, whereas its expression was homogeneous in benign melanomas.
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PMID:Differential expression of CD44 in canine melanocytic tumours. 1500 75

Heat shock proteins (HSPs) exist ubiquitously across all species and function as chaperones stabilizing and delivering peptides. Tumor-derived HSP-peptide complex has been known to induce immunity against the original tumor in preclinical studies. HSP-based vaccines work across tumor types and bypass the need for identifying the responsible peptide(s) for inducing immunity. These vaccines are tumor- and patient-specific in that they capture the tumor cells' fingerprints. HSP-based vaccines have been studied in early phase clinical trials, mostly using HSP glycoprotein 96, for various types of malignancies including melanoma, renal cell carcinoma, gastric cancer, pancreatic cancer, low-grade lymphoma, colorectal cancer and chronic myelogenous leukemia. All showed minimal toxicity and potential efficacy. Phase III studies for melanoma and renal cell carcinoma are ongoing. HSP-based vaccines are a novel vaccine preparation with a promising role in cancer management. Further studies to determine the administering strategy and specific indication are warranted.
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PMID:Heat shock protein-based cancer vaccines. 1527 Jun 45

In order to assess the contribution of FC to the diagnosis of lymph node disorders we retrospectively compared the pathological and the FC diagnosis made in 118 consecutive lymph node biopsies. Pathological diagnosis included non malignant conditions (n = 43), B-cell Non Hodgkin lymphoma (NHL) (n = 30), T-cell NHL (1 case), carcinoma (n = 18), Hodgkin lymphoma (HL) (n = 15), melanoma (n = 2), chronic myelocytic leukemia (n = 12), miscellaneous non-lymphoid tissues (n = 6) and undetermined conditions (n = 2). Among the 116 assessable samples, FC was in agreement with histology in 102 cases (87.9%; 95%CI = 81-93) which included 38 benign conditions (90%; 95% CI = 77-97%), 29 NHL (96.7%; 95% CI = 83-100), 18 carcinomas (100%; 95% CI = 81-100), and 12 HL (80.0%; 95% CI = 52-96). Discrepancies (14 cases) included 3 HL undiagnosed by FC and 2 granulomatous adenitis with an erroneous FC diagnosis of HL. Finally, a malignant condition was suspected only by FC in 5 cases (1 carcinoma, 2 B-cell and 2 T-cell NHL) and subsequently demonstrated by additional diagnostic procedures. In conclusion, this study confirms that FC performed on fresh lymph node samples is a powerful diagnostic tool in patients with malignant lymphoma. A few cases left undiagnosed by classical pathological analysis can be recognized by FC. Carcinoma is readily identified by FC analysis, while some benign conditions and Hodgkin lymphoma can be misdiagnosed with the use of FC, although the potential of FC to properly recognize HL is improving compared to previously reported studies. FC is a useful adjunct to pathological analysis of lymph node specimens.
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PMID:Contribution of flow cytometry to the diagnosis of malignant and non malignant conditions in lymph node biopsies. 1537 Feb 10

Betulinic acid (BA), a plant derived triterpenoid, isolated from various sources shows cytotoxicity in cell lines of melanoma, neuroectodermal and malignant brain tumors. Chronic myelogenous leukemia (CML) is characterized by Philadelphia chromosome (Bcr-Abl), a molecular abnormality leading to the intrinsic tyrosine kinase activity that provides growth and survival advantage to the cells. Present study describes the cytotoxicity of BA on human CML cell line K-562, positive for Bcr-Abl. The decrease in the viability of K-562 cells treated with BA at different concentrations and time intervals was assessed using MTT assay. Cell death induced by BA was determined to be apoptotic as measured by FACS analysis of PI stained nuclei, PS externalization by Annexin-V fluorescence and characteristic DNA fragmentation. DiOC6(3) fluorescent probe determined alterations in the mitochondrial membrane potential (MMP). RT-PCR confirmed the expression levels of Bcr-Abl in controls and K-562 cells treated with BA. The rapid loss of MMP of K-562 cells upon treatment with BA shows the direct activation of apoptosis at the level of mitochondria, overcoming the resistance of the high levels of expression of Bcr-Abl.
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PMID:Betulinic acid induces apoptosis in human chronic myelogenous leukemia (CML) cell line K-562 without altering the levels of Bcr-Abl. 1564 17

Various drugs have been associated with the development of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Among the biologic agents, alpha-interferon therapy, used for treatment of hepatitis B and chronic myelogenous leukemia, has been associated with TTP in a few recent reports. The authors report the first case of TTP/HUS occurring in a metastatic melanoma patient receiving treatment with high-dose interleukin-2 (IL-2). A 57-year-old patient with malignant melanoma presented with seizures 3 days after completing the first week of high-dose IL-2, and the characteristic hematologic picture revealed TTP/HUS. This occurrence is unlikely to be explained by the association with malignant melanoma, which was not presenting with widespread visceral disease at the time of the occurrence, or by the use of other medications. Similar cytokine release profiles are encountered in TTP, HUS caused by Shiga toxin-1, HUS caused by E. coli O157, after IL-2 or IL-2-containing biochemotherapy, as well as in TTP caused by interferon-alpha. This cytokine profile could reflect a common cause, or just the presence of similar pathways involved.
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PMID:Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome associated with high-dose interleukin-2 for the treatment of metastatic melanoma. 1572 58

This study was conducted to determine the outcome of patients who develop a second neoplasm after radiotherapy (RT) for a childhood solid tumor. From 1956 to 1998, 429 children with a malignant solid tumor were treated at a single radiation oncology facility. The medical records and radiotherapy charts were reviewed to determine if the patient developed a secondary neoplasm after treatment for malignancy. Twenty-three (5.4%) patients developed a secondary neoplasm. There were 12 males and 11 females with a median age at RT of 6.6 years (range, 2 months to 20 years). There were 14 malignant neoplasms in 13 (3.0%) and 14 benign neoplasms in 11 patients (2.6%). The types of initial solid tumors treated with RT were Ewing sarcoma in 6, Wilms tumor in 6, medulloblastoma in 5, neuroblastoma in 3, and other in 3. Median RT dose was 45 Gy (range, 12.3 to 60 Gy) using 4 MV in 9, 1.25 MV in 8, 250 KV in 4, and 6 MV photons in 1 patient. One child was treated using 15-MeV electrons. Fourteen had chemotherapy. Median follow-up was 23.2 years (range, 5.3 to 44.4 years). For the 14 malignant neoplasms, the median time interval from initial tumor to second malignancy was 10.1 years. The 14 second malignant neoplasms (SMN) were osteosarcoma in 3, breast carcinoma in 2, melanoma in 2, malignant fibrous histiocytoma in 1, dermatofibrosarcoma in 1, leiomyosarcoma in 1, mucoepidermoid carcinoma in 1, colon cancer in 1, chronic myelogenous leukemia in 1, and basal cell carcinoma in 1. Ten of the 14 SMN (71%) were at the edge or inside the RT field. The 5- and 10-year overall survival rate after diagnosis of an SMN was 69.2%; it was 70% for children with a SMN at the edge or inside the RT field and 66.7% for those outside of the RT field. The 14 benign neoplasms appeared at a median time of 16.9 years and included cervical intraepithelial neoplasia in 3, osteochondroma in 3, thyroid adenoma in 1, duodenal adenoma in 1, lipoma in 1, cherry angioma in 1, uterine leiomyoma in 1, ovarian cystadenofibroma in 1, and giant cell tumor in 1. Only 5 (36%) of the 14 benign tumors occurred in the RT field, with osteochondroma being the most common. Of 189 deaths occurring in 429 patients, only 3 (1.6%) were secondary to radiation-induced malignancy. Not all SMN in children receiving RT occur in the irradiated field. More than two-thirds of children with a radiation-induced malignancy are alive 10 years after the diagnosis of a SMN.
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PMID:Secondary neoplasms after radiotherapy for a childhood solid tumor. 1580 94


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