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)

Imatinib mesylate (imatinib) is an orally administered competitive inhibitor of the tyrosine kinases associated with the KIT protein (stem cell factor receptor), ABL protein and platelet-derived growth factor receptors. The KIT tyrosine kinase is abnormally expressed in gastrointestinal stromal tumour (GIST), a rare neoplasm for which there has been no effective systemic therapy. In a randomised, nonblind, multicentre study that evaluated imatinib 400 or 600mg once daily in 147 patients with advanced GIST, confirmed partial responses were achieved in 54% of patients overall (median duration of follow-up was 288 days). Stable disease was experienced by 28% of patients and the estimated 1-year survival rate was 88%. Similar response rates were reported in a smaller, dose-escalation study, in which objective tumour response was a secondary endpoint. Although nearly all patients with GIST treated with imatinib experienced adverse events, most events were mild or moderate in nature. Severe or serious adverse events occurred in 21% of patients in the larger study, and included gastrointestinal or tumour haemorrhage. The control of cellular processes, such as cell growth, division and death, involves signal transduction, which commonly involves the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues on substrate proteins, by tyrosine kinase enzymes. Activation of oncogenes coding for kinase proteins can lead to the production of kinases that are continually active in the absence of a normal stimulus,leading to increased cell proliferation and/or decreased apoptosis. A major focus of cancer research in recent years has been to identify oncogenic molecules and the signal transduction pathways in which they are involved, in order to develop specifically targeted drugs. One such drug is imatinib mesylate (imatinib, Glivic/Gleevec), an orally administered 2-phenylaminopyrimidine derivative that is a competitive inhibitor of the tyrosine kinases associated with platelet-derived growth factor (PDGF) receptors, the Abelson (ABL) protein and the KIT protein (also known as stem cell factor [SCF] receptor). Imatinib was initially evaluated for the treatment of chronic myeloid leukaemia (CML) [reviewed previously in Drugs]. More recently, imatinib has been approved for the treatment of patients with advanced gastrointestinal stromal tumour (GIST), in which KIT, a tyrosine kinase receptor, is abnormally expressed. GISTs are soft tissue gastrointestinal sarcomas probably arising from mesenchymal cells. They are rare neoplasms, with between 5000 and 10 000 new cases being diagnosed each year in the US. GISTs occur throughout the gastrointestinal tract but the stomach and small intestine are the most common sites. Symptoms depend on the site and size of the tumour, and may include abdominal pain, gastrointestinal bleeding or signs of obstruction; small tumours may be asymptomatic. The diagnosis of GIST is made by immunohistochemical staining for CD117, a cell surface antigen on the extracellular domain of KIT, in conjunction with pathological examination of tissue with light microscopy. All GISTs may have some degree of malignant potential. They are unresponsive to standard chemotherapy and to radiotherapy, and the mainstay of treatment in the past has been surgery. However, recurrence rates are high, and there has been no effective systemic treatment for unresectable GIST or metastatic disease. For patients in whom complete resection is not possible, or in patients with metastatic or recurrent disease, the median duration of survival is 9-12 months, and 10-19 months, respectively. Gain-of-function mutations of the KIT proto-oncogene occur in up to 90% of GISTs, allowing constitutive activation of tyrosine kinase (i.e. auto-phosphorylation of tyrosine residues independent of ligand-receptor binding), leading to aberrant cell division and tumour growth. Imatinib selectively inhibits the tyrosine kinase activity associated with KIT, which forms the rationale for evaluating its effects in GIST. Subsequent to initial evidence of the clinical efficacy of imatinib in a single patient with progressive, metastatic, CD117-positive GIST, formal studies of imatinib in this new indication were initiated. This article summarises the pharmacology, efficacy and tolerability profile of imatinib in the treatment of patients with advanced GIST.
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PMID:Imatinib mesylate: in the treatment of gastrointestinal stromal tumours. 1260 Feb 28

Multiple myeloma (MM) is the most common plasma cell dyscrasia. Conventional therapy results in a median survival of 3-5 years. Patients with B-cell disorders and coexistent HER-2/neu overexpression in solid tumors have a poorer prognosis than those without an underlying B-cell disorder. This, and the recent success of the tyrosine kinase inhibitor, imatinib mesylate in chronic myelogenous leukemia, led us to evaluate the incidence and role of c-kit (CD117) and HER-2/neu overexpression in MM. We conducted a retrospective study to determine the incidence of HER-2/neu and c-kit overexpression in MM. HER-2/neu overexpression was evaluated using the DAKO Hercep test and c-kit overexpression was assessed using conventional immunohistochemistry (IHC); 69 patients with a diagnosis of MM were identified, of whom, 31 patients (19 males and 12 females) had an adequate pathological specimen available for IHC testing; 4 out of 31 patients (12.9%) showed HER-2/neu overexpression, while 5/31 (16.13%) showed CD117 expression. Two patients (6.45%) showed both HER-2/neu and c-kit overexpression. Although both HER-2/neu and c-kit are not expressed very frequently in patients with MM, there appears to be a subgroup of patients in whom, either one or both these oncogenes is overexpressed. Given our small sample size, it is difficult to comment on the effect of CD117 and/or HER-2/neu overexpression on survival. Future larger studies are needed to define the association in MM and to determine if the presence of one (CD117 or HER-2/neu) has an effect on overexpression of the other oncoprotein. Furthermore, it would be beneficial to identify the molecular nature of the interplay between HER-2/neu and c-kit, if any. Target-directed signal transduction inhibition therapy using tyrosine kinase inhibitors, may be a distinct possibility in a select group of patients with MM.
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PMID:Immunohistochemical identification of HER-2/neu overexpression and CD117 (c-kit) expression in multiple myeloma. 1261 38

c-Kit receptor (CD117) is expressed by erythroid, megakaryocytic, and myeloid precursors and mature mast cells and has been reported to be expressed in CD30+ lymphomas such as Hodgkin's disease and anaplastic large-cell lymphoma. Imatinib mesylate, a well-established inhibitor of bcr-abl tyrosine kinase, and currently used for the treatment of patients with chronic myeloid leukemia, also inhibits c-kit receptor kinase activity. In view of the possible use of imatinib as experimental therapy for patients with c-kit-positive tumors, we assessed c-kit expression in CD30+ cell lines and lymphomas. The cell lines were assessed using multiple methods (RT-PCR, flow cytometry, and Western blot). c-Kit expression was also immunohistochemically assessed in 168 CD30+ lymphomas including 87 classical Hodgkin's disease, 63 anaplastic large-cell lymphoma, and 15 cutaneous anaplastic large-cell lymphoma. We also studied 18 cases of lymphomatoid papulosis, a CD30+ lesion closely related to cutaneous anaplastic large-cell lymphoma. Neither c-kit mRNA nor protein was detected in any of the cell lines assessed. Furthermore, treatment with imatinib did not inhibit proliferation of cell lines in vitro. Using immunohistochemistry, only one of 183 (0.5%) lesions was positive for c-kit, the positive case being an ALK-negative anaplastic large-cell lymphoma. Our data demonstrate that expression of c-kit receptor is exceedingly rare among CD30+ lymphomas and lymphomatoid papulosis, suggesting that c-kit receptor is unlikely to be an appropriate target for therapeutic options such as imatinib in patients with these tumors.
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PMID:Lack of c-kit (CD117) expression in CD30+ lymphomas and lymphomatoid papulosis. 1510 13

A specific treatment for gastrointestinal stromal tumors (GIST) has been found through improved understanding of the molecular mechanism of carcinogenesis. GIST are radio and chemo-resistant (less than 10 objective responses). Stromal tumors originate from the multiplication of the cells of Cajal, which intervene in intestinal motility and express the c-Kit gene, also called CD117, on their surface. CD117 is a protein with tyrosine kinase activity, and can be demonstrated through immunohistochemical staining techniques. Treatment with Imatinib mesylate (Glivec), a recently discovered selective inhibitor of tyrosine kinases already used in chronic myeloid leukemia (in which an overexpression of tyrosine kinase is observed) was associated with tumor regression of more than 50% in the initial series of patients with GIST treated in 2001. Since then, approximately 2,000 patients have been included in therapeutic trials, with an objective response rate between 60% and 70% 12 to 18 months after inclusion. The clinical benefit has been estimated at 80% to 90% in patients whose chance of survival until now has been less than 30% at one year (median survival 18 months). Nonetheless, imatinib mesylate has not shown any activity in CD117-negative sarcoma (10% of sarcoma). The therapeutic importance of this drug in the treatment of solid GI tumors deemed inoperable is considerable.
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PMID:Treatment of gastrointestinal stromal tumors with imatinib mesylate: a major breakthrough in the understanding of tumor-specific molecular characteristics. 1570 44

C-kit is a tyrosine kinase receptor which is expressed in a wide variety of tumour cells such as gastrointestinal stromal tumours (GISTs), germ cell tumours, malignant trans-formation of mast cells, breast adenocarcinomas, malignant melanomas and small cell lung cancers. Imatinib mesylate is a tyrosine kinase inhibitor initially developed against the bcr-abl fusion protein of CML, but also shows therapeutic inhibitory activity against c-Kit expressed in GISTs. Treatment of patients with neuroendocrine tumours (NETs) at present is limited. Our aim was to test NETs for c-Kit expression and hence identify patients for the consideration of therapy with imatinib mesylate. NET patient specimens (n=85) were assessed for expression of c-KIT proto-oncogene (CD117) by immunohistochemistry using two antibodies, a polyclonal antibody and a monoclonal. Of the samples 24% stained positive with the polyclonal antibody and 64% with the monoclonal antibody. This study highlights problems related to screening using c-kit antibodies for immunocytochemistry. It is possible that the polyclonal antibody is less specific. Studies need to be performed to determine if c-kit expression by NETs can be translated into therapeutic benefit by agents such as imatinib mesylate.
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PMID:Expression of c-kit (CD117) in neuroendocrine tumours--a target for therapy? 1575 36

PBT-3 is one of a family of stable chemical analogs of the hepoxilins, products derived from arachidonic acid. We previously showed that PBT-3 caused apoptosis in the chronic myelogenous leukemia (CML) cell line K-562 in vitro (Anti-cancer Res 23: 3617-3622, 2003). It was as effective as Gleevec, a novel agent that blocks tyrosine kinase activity during treatment of CML. We describe, herein, the growth inhibiting effects of PBT-3 in nude mice into which K-562 cells were transplanted subcutaneously. Groups of mice were treated with vehicle as control, or PBT-3, or Gleevec. PBT-3 was effective during the 8-day treatment protocol in inhibiting the growth of the tumours in vivo as was Gleevec. Analysis of the tumours demonstrated the presence of apoptosis (DNA laddering and TUNEL assay) in both the PBT-3- and Gleevec-treated groups. These results demonstrate that PBT-3 is effective in vivo in controlling tumour growth and provides a novel platform for the therapeutic control of cancer.
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PMID:The hepoxilin analog, PBT-3, inhibits growth of K-562 CML solid tumours in vivo in nude mice. 1579 72

Recent data suggest that myeloid neoplasms are organized hierarchically in terms of self-renewal and maturation of early progenitor cells, similar to normal myelopoiesis. In acute myeloid leukemia (AML), the NOD/SCID mouse-repopulating leukemic stem cells usually co-express CD123 with CD34, but lack CD38. So far, however, little is known about expression of other markers and targets on these progenitors. In the present study, expression of target antigens on CD34+/CD38- cells was analysed by multi-color flow cytometry in patients with AML (n = 18), myelodysplastic syndromes (MDS, n = 6), chronic myeloid leukemia (CML, n = 8) and systemic mastocytosis (SM, n = 9). The IL-3Ralpha chain (CD123) was found to be expressed on CD34+/CD38- cells in a majority of the patients in all disease categories. Independent of the type of disease, the vast majority of these stem cells co-expressed aminopeptidase-N (CD13) and CD44 in all patients. By contrast, the CD34+/CD38- progenitor cells expressed variable amounts of the target receptor CD33, c-kit (CD117) and AC133 (CD133). In conclusion, neoplastic stem cells in various myeloid neoplasms appear to express a similar phenotype including target antigens such as CD13, CD33 and CD44. Since many of these targets are not expressed on all stem cells in all patients, the elimination of the entire clone may require combinations of targeted antibodies or use of additional drugs.
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PMID:Detection of molecular targets on the surface of CD34+/CD38-- stem cells in various myeloid malignancies. 1632 50

The aim of this study was to evaluate the value of CD117/CD11b phenotypic analysis to diagnosis and prognosis of acute promyelocytic leukemia (APL). Three- or four-color flow cytometry with a series of 22 monoclonal antibodies and CD45/Side Scatter (SSC) gating strategy were used to identify immunophenotypic characteristics of APL as compared to CML in chronic phase (CML-CP). PML/RAR alpha fusion gene was detected by using reverse-transcription polymerase chain reaction (RT-PCR) technique. The results showed that MPO, CD13 and CD33 were almost expressed in all patients with APL and CML-CP whereas HLA-DR and CD34, the hematopoietic progenitor cell markers, were rarely expressed. The positive rate of CD15 in APL was significantly lower than those in CML-CP (P < 0.01). CD117 was positive in 78.3% of the APL cases and in none of the cases of CML-CP. On the other hand, CD11b was almost positive in all cases of CML-CP, but only 16.9% of the APL cases were found positive for this antigen. The CD117+ CD11b- phenotype was present in 72.3% of APL cases while none of cases with CML-CP with this phenotype. Almost all of the cases with CML-CP had the phenotype of CD117- CD11b+. CD117- CD11b+ phenotype was detected in all patients recovering from APL with CD117+ CD11b- phenotype at diagnosis and after treatment with all-trans-retinoic acid (ARTA) for 2 months. PML/RAR alpha fusion gene was positive in 80.6% (25/31) of the APL cases, of which, 64% of the cases belonged to the type L while only 36% of the cases were showed type S for this fusion gene. The positive rates of CD117 were 87.5%, 44.4% and 33.3% in type L group, S group and negative group respectively. It is concluded that analysis of both CD117 and CD11b phenotype may be helpful to the diagnosis, therapy and prognosis of APL in children and adults and to differentiation of APL from recovering benign myeloid proliferation.
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PMID:[Expressions of CD117 and CD11b in patients with APL at diagnosis and post-treatment]. 1692 91

Varicella zoster virus (VZV) infection is uncommon in patients with gastrointestinal stromal tumour (GIST) and who have not been exposed to extensive radiotherapy and/or high-dose chemotherapy. We report a 56-year-old Nigerian man with GIST who developed VZV infection while on imatinib mesylate therapy. From August 2003 to November 2005, 64 patients (GIST/CML = 6/58) were enrolled into an ongoing Glivec (imatinib mesylate) international patient-assistance programme therapy for Philadelphia/bcr-abl-positive chronic myeloid leukaemia (CML) and CD117-positive GIST patients at Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria. The patient developed herpes zoster (HZ) infection 23 months into therapy with Glivec. With his absolute lymphocyte count at 2,774 cells per microlitre and CD4 count at 950 cells per microlitre, no obvious immunological defect was observed. Prompt resolution of symptoms without sequelae was achieved by treating with acyclovir, analgesic and dressing of lesions with desiccant. To our knowledge, this is the first reported case of HZ infection in a patient with GIST on Glivec therapy, and the response is similar to that of CML patients who developed VZV while on similar therapy.
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PMID:Herpes zoster complicating imatinib mesylate for gastrointestinal stromal tumour. 1724 98

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract that are believed to originate from a neoplastic transformation of the intestinal pacemaker cells (interstitial cells of Cajal) normally found in the bowel wall or their precursors. Although the microscopic features have been known for a long time, the defining characteristic of GIST is the presence of the cell-surface antigen CD117 (KIT), which is demonstrated by immunohistochemistry. KIT, which is a growth factor transmembrane receptor, is the product of the proto-oncogene c-kit (chromosome 4). Surgical removal remains the only curative treatment for patients with GISTs. Tumor size, mitotic index, anatomic location, tumor rupture and disease-free interval are the classic characteristics used to predict the clinical course of patients who undergo complete gross resection. Most GISTs express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. Imatinib mesylate is a rationally designed, molecularly specific oral anticancer agent that selectively inhibits several protein tyrosine kinases central to the pathogenesis of human cancer and which has demonstrated remarkable clinical efficacy in patients with chronic myeloid leukemia and malignant GISTs. More recently Sunitinib, a new KIT/PDGFRA kinase inhibitor, has been tested in patients with GIST resistant to imatinib, with promising results.
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PMID:Gastrointestinal stromal tumors (GISTs): focus on histopathological diagnosis and biomolecular features. 1759 8


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