Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal (GI) tract. The c-kit receptor tyrosine kinase (KIT) is expressed by practically all GISTs, and gain-of-function mutations of KIT are present in most GISTs. Interstitial cells of Cajal (ICC) are the pacemaker of the peristaltic movement of the GI tract. Since signals through KIT are essential for development of ICC and since multiple GISTs develop from the hyperplastic lesion of ICCs in familial GIST patients with germline mutations of KIT, GISTs are considered to originate from ICC. Imatinib mesylate, which was developed for treatment of chronic myeloid leukemia (CML), was found to be useful for treatment of GISTs. Imatinib mesylate inhibits BCR-ABL fused tyrosine kinase that causes CML. Imatinib mesylate also inhibits the mutated KIT observed in most GISTs, and this explains the effectiveness of Imatinib mesylate on GISTs. GISTs appear to serve as a model for molecule-based diagnosis and treatment of solid tumors.
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PMID:Gastrointestinal stromal tumors (GIST): a model for molecule-based diagnosis and treatment of solid tumors. 1282 97

Previous studies suggested that the SH2-containing inositol-5-phosphatase (SHIP) may play a tumor suppressor-like function in BCR-ABL-mediated leukemogenesis. To investigate this possibility, we first developed a new assay for quantitating transplantable multilineage leukemia-initiating cells (L-ICs) in hematopoietic stem cell (HSC)-enriched mouse bone marrow (BM) cells transduced with a BCR-ABL-GFP (green fluorescent protein) retrovirus. The frequency of L-ICs (1 of 430 Sca-1+lin- cells) was 7-fold lower than the frequency of HSCs in the Sca-1+lin- subset transduced with a control virus (1 of 65 cells). Forced BCRABL expression was also accompanied by a loss of regular HSC activity consistent with the acquisition of an increased probability of differentiation. Interestingly, the frequency and in vivo behavior of wild-type (+/+) and SHIP-/- L-ICs were indistinguishable, and in vitro, Sca-1+lin- BCR-ABL-transduced SHIP-/- cells showed a modestly reduced factor independence. Comparison of different populations of cells from patients with chronic myeloid leukemia (CML) in chronic phase and normal human BM showed that the reduced expression of full-length SHIP proteins seen in the more mature (CD34-lin+) leukemic cells is not mirrored in the more primitive (CD34+lin-) leukemic cells. Thus, SHIP expression appears to be differently altered in the early and late stages of differentiation of BCR-ABL-transformed cells, underscoring the importance of the cellular context in which its mechanistic effects are analyzed.
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PMID:Evidence for a positive role of SHIP in the BCR-ABL-mediated transformation of primitive murine hematopoietic cells and in human chronic myeloid leukemia. 1282 95

Resistance to chronic myeloid leukemia (CML) drug STI571 has been associated with point mutations in the kinase domain of BCR-ABL. For example, the mutation T315I (g. 68721C>T) and, to a lesser extent, Y253F (g. 58796A>T) appear in a significant proportion of patients resistant to treatment. Mutations appear intimately related to the development of resistance, and they may pre-exist in a small percentage (<1%) of tumor cells at the time of treatment initiation. Most mutation detection methods, including sequencing, are unable to detect such a small percentage of mutations in a background of wild type sequences. We describe the simplification and modification of a recently developed enhanced PCR-RFLP method, and its application to the detection of T315I and Y253F mutations. The method is quantitative, can be used in agarose gel or real time PCR formats, and reliably detects 1 mutation-containing cell in a background of almost 1000 non-mutated cells. The increased sensitivity offered by this assay will allow detection of these mutations at an early stage during treatment and will be useful in rational treatment modification and in studies which address the association between these mutations and drug resistance.
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PMID:Sensitive and quantitative detection of mutations associated with clinical resistance to STI-571. 1285 90

Imatinib mesylate (Gleevec) inhibits the BCR-ABL tyrosine kinase in chronic granulocytic leukemia. Previous studies have demonstrated that imatinib mesylate also inhibits the survival and functions of normal mast cells by interfering with the receptor tyrosine kinase for stem cell factor (SCF), c-kit, which is expressed by mast cells. Because mast cells extensively surround many types of cancer and contain powerful anticoagulants such as heparin, we investigated the effects of imatinib mesylate on blood clotting and tumor growth within subcutaneous implants of a mammary adenocarcinoma cell line (4T1) in BALB/c mice. After 5 days of oral treatment with 10 mg/kg of the drug, the average mass of the tumors in treated mice (198 +/- 42 mg, n = 5) was significantly (p < 0.05) greater than the average mass of the tumors from untreated (control) mice (60 +/- 23 mg, n = 5). Moreover, the tumors in the treated mice were frequently surrounded by large lakes of clotted blood that were not evident in tumors from the control mice. Accelerated growth and blood clotting were also observed in tumor-bearing mice treated with heparinase I enzyme to destroy endogenous mast cell heparin and in NDST-2 knockout mice in which there is a targeted disruption in the gene coding for mast cell heparin synthesis. We conclude that imatinib mesylate accelerated the growth and peri-tumoral blood clotting of implants of mammary adenocarcinoma in mice. These results suggest that imatinib mesylate may have significant effects on mast cells infiltrating tumors, in addition to its other biologic activities. Our results also indicate that the mechanism of this effect may be related to the anticoagulant properties of mast cell heparin.
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PMID:Acceleration of tumor growth and peri-tumoral blood clotting by imatinib mesylate (Gleevec). 1286 22

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors. The molecular etiology is the result of mutations in the c-Kit gene. The mutant c-Kit proteins, which are activated without a stem cell factor, contribute to the tumor development. STI571 selectively inhibits c-Kit, BCR-ABL, and PDGFR tyrosine kinases. Based on this potential to inhibit critical c-Kit function in GISTs, case studies have reported effective outcomes following treatment with STI571. This case report describes a highly effective use of STI571 in a 54-year-old woman with multiple liver metastases from a GIST originating in the duodenum.
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PMID:Effect of a tyrosine kinase inhibitor STI571 in a patient with hepatic metastases from a duodenal gastrointestinal stromal tumor. 1289 63

The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 microM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21(CIP1) and p27(KIP1). These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.
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PMID:Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways. 1291 35

Diagnosis of chronic myeloid leukemia and acute lymphoblastic leukemia requires the investigation of the Philadelphia chromosome translocation t(9;22) or the molecular detection of BCR-ABL fusion transcripts. Determination of the type of fusion transcript is crucial for quantitative molecular monitoring the course of the disease during treatment. Histopathologists, who usually use formalin-fixed tissues, may be confronted with the need to investigate the BCR-ABL rearrangement when evaluating tumor forming infiltrates and bone marrow trephines from patients presenting with chronic myeloproliferative disorders. Therefore, we have established a one-tube multiplex RT-PCR for the detection of common BCR-ABL fusion transcripts (b2a2, b3a2, e1a2) in routinely processed tissues and bone marrow trephines with respect to the inevitable fragmentation of ribonucleic acids in these specimens. RT-PCR products allow distinct and unequivocal differentiation of the underlying fusion in either the Major- or minor-breakpoint cluster region. Detection of BCR-ABL fusion transcripts by multiplex RT-PCR in routinely processed and fixed tissues is a time- and cost-sparing tool for definite diagnosis of typical chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia.
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PMID:Multiplex RT-PCR for the detection of common BCR-ABL fusion transcripts in paraffin-embedded tissues from patients with chronic myeloid leukemia and acute lymphoblastic leukemia. 1296 Jun 92

The regulation of graft-versus-host disease (GVHD) and graft-versus-leukemia/tumor (GVL/T) effect is the most important issue in allogeneic stem cell transplantation. Although it is very difficult to separate GVHD and GVL/T, however, we should try to find the way to suppress GVHD and induce GVL/T at the same time. From that point of view, the induction of CTL against minor histocompatibility antigens such as HA-1 and tumor specific antigens such as BCR-ABL chimeric protein may be useful. Also, the new concept of alloreactive NK cells which have inhibitory NK cell receptor seem to be interesting to regulate GVHD and GVL/T. Further study is needed to establish new allogeneic cell therapy to obtain the clinical improvement.
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PMID:[Target antigens for graft-versus-host disease (GVHD) and graft-versus-leukemia/tumor (GVL/T)]. 1451 17

The interferon treatment of chronic myeloid leukaemia has been monitored by investigating the tumour burden as revealed by fluorescence in situ hybridization and the expression of BCR-ABL chimera determined by quantitative reverse transcription polymerase chain reaction. These parameters were obtained from the peripheral blood of 51 untreated and 104 follow-up patient samples. Poor correlation (r=0.31) was found between BCR-ABL expression and tumor load in all samples as well as in untreated patients, and this correlation was even less in all follow-up cases (r=0.28). Regarding chimera expression five order of magnitude difference existed in the untreated patients and this value dropped to two in those with complete cytogenetic response. Only the major and the complete cytogenetic response groups differed significantly (p<0.001) in the BCR-ABL expression from that of patients at diagnosis. Among the different cytogenetic response groups the only significant difference (p<0.01) in the BCRABL expression was obtained between the major and the minor responders. In the individual patients not only correlated changes of residual tumour mass and chimera expression, but mainly independent changes of these two parameters were observed. This indicates that the BCR-ABL expression and the tumor burden are largely independent variables.
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PMID:Correlation between BCR-ABL expression and tumor burden is restricted to the transition from minor to major cytogenetic response in interferon treated CML patients. 1453 Aug 11

Cancer is also an epigenetic disease. The main epigenetic modification in humans is DNA methylation. Transformed cells undergo a dramatic change in their DNA methylation patterns: certain CpG islands located in the promoter regions of tumor-suppressor genes become hypermethylated and the contiguous gene rests silenced and this phenomenon occurs in an overall genomic environment of DNA hypomethylation. The profile of CpG island hypermethylation in hematologic malignancies is an epigenetic signature unique for each subtype of leukemia or lymphoma. Although the most widely studied genes are the cell-cycle inhibitors p15INK4b and p16INK4a (specially in AML and ALL), the list of methylation-repressed genes in these neoplasms is expanding very rapidly, including MGMT, RARB2, CRBP1, SOCS-1, CDH1, DAPK1, and others. A necessary cross-talk between genetic alterations and DNA methylation exists: certain chromosomal translocations may induce hypermethylation, such as the PML-RARa, or attract methylation, such as BCR-ABL, but DNA hypomethylation can be the culprit behind the genesis of certain abnormal recombination events. From a translational standpoint, hypermethylation can be used as a marker of recurrent disease or progression, for example, in MDS, or response to chemotherapy, such as MGMT methylation in B-cell non-Hodgkin's lymphoma. Furthermore, promising studies using DNA demethylating agents and histone deacetylase inhibitors are underway to awake these dormant tumor-suppressor genes for a better treatment of the patient with a hematologic malignancy.
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PMID:Profiling aberrant DNA methylation in hematologic neoplasms: a view from the tip of the iceberg. 1458 79


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