Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemokine receptor, CXCR4, is a GPCR that transduces signals of its endogenous ligand, CXCL12 (stromal cell-derived factor-1, SDF-1). The CXCL12-CXCR4 system plays an important role in the migration of progenitors during embryologic development of the cardiovascular, hemopoietic, central nervous systems, etc. This system has recently been proven to be involved in several problematic diseases, including HIV infection, cancer cell metastasis, leukemia cell progression, rheumatoid arthritis (RA) and pulmonary fibrosis. Thus, CXCR4 is thought to be an important therapeutic target to overcome the above diseases. Fourteen-mer peptides, T140 and its analogs, were previously found to be specific CXCR4 antagonists that were characterized as HIV-entry inhibitors, anti-cancer-metastatic agents, anti-chronic lymphocytic/acute lymphoblastic leukemia agents and anti-RA agents. Based on our knowledge of pharmacophores of T140, CXCR4 antagonists, such as FC131, were previously found by the efficient utilization of cyclic pentapeptide libraries. This review article focuses on our recent research on the development of low molecular weight CXCR4 antagonists including FC131 analogs, in which structural tuning of the cyclic peptide ring and chemical modifications were performed for an increase in potency and a reduction of the peptide character.
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PMID:Development of low molecular weight CXCR4 antagonists by exploratory structural tuning of cyclic tetra- and pentapeptide-scaffolds towards the treatment of HIV infection, cancer metastasis and rheumatoid arthritis. 1726 70

Plerixafor [Mozobil, AMD 3100, JM 3100, SDZ SID 791] is a bicyclam derivative that acts as a stem cell mobiliser by blocking the CXCR4 chemokine receptor. Plerixafor was synthesised by Johnson Matthey (AnorMED) in collaboration with the Rega Institute of Leuven, Belgium. Plerixafor is in phase III clinical trials in stem cell transplantation among cancer patients. Plerixafor blocks CXCR4, which triggers the rapid movement of stem cells out of the bone marrow and into circulating blood. These cells can then be collected and used in stem cell transplant procedures. Plerixafor had been available for partnering in Europe. However, decisions concerning partnering arrangements were deferred by AnorMED until top-line clinical data became available (expected in 2007). In November 2006, Genzyme Corporation completed its acquisition of AnorMED. Genzyme intends to commercialise plerixafor in >50 countries throughout the world using its existing transplant business. Evotec OAI was selected by AnorMED to support it in the chemical development of plerixafor. Evotec OAI will use EVOdevelop, its integrated chemical and pharmaceutical development platform, to complete the full validation of the process to plerixafor, including process research and development, cGMP manufacturing and analytical work. Evotec OAI will also be responsible for producing the relevant Chemical Manufacturing Control (CMC) documentation for regulatory filings. Top line results from the phase III studies are expected in the second quarter of 2007 and, assuming these are successful, the marketing submissions are planned for the US in 2007 (launch in 2008), and for Canada and Europe in 2008. Plerixafor has orphan drug status for stem cell transplantation in cancer patients in the US and the EU. AnorMED (now Genzyme) decided to pursue a full Marketing Authorisation Application (MAA) in Europe for plerixafor in stem cell transplant. Previously, the company had been planning on filing a CMA (Conditional Marketing Authorisation) in this region. The change in strategy requires additional phase II trials in the five major EU markets. Multicentre phase II trials with plerixafor have begun in Canada and Germany in approximately 50 patients with non-Hodgkin's lymphoma and multiple myeloma (studies EU21 and C201). Enrolment has been completed in a US-based, multicentre, phase II trial (study 2105) of plerixafor plus G-CSF in patients with multiple myeloma and non-Hodgkin's lymphoma. This study is designed to optimise the administration schedule of this combination therapy regimen. Plerixafor has completed a phase II study (study 2104) in multiple myeloma and NHL patients in combination with chemotherapy. A US-based phase II pilot study (study 2108) with plerixafor as a single mobilising agent in multiple myeloma patients undergoing stem cell transplant is underway. Another US-based phase II pilot study (study 2106) is evaluating plerixafor in combination with the standard mobilisation regimen, G-CSF, in patients with Hodgkin's disease undergoing stem cell transplant. AnorMED completed a phase II study (study 2101) evaluating the potential of plerixafor in combination with G-CSF as a therapy for stem cell transplantation compared to G-CSF therapy alone. The study involved patients with multiple myeloma and patients with NHL. Results indicated that the combination regimen was significantly superior to G-CSF treatment alone in stem cell mobilisation. Further trials are planned for plerixafor, to expand its use in transplant and in other indications including one to investigate the potential of plerixafor to improve the effectiveness of chemotherapy in patients with leukaemia. Phase I trials have been completed.
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PMID:Plerixafor: AMD 3100, AMD3100, JM 3100, SDZ SID 791. 1732 9

Expression of chemokine receptors by tumors, specifically CCR4 on cutaneous T cell lymphomas, is often associated with a poor disease outcome. To test the hypothesis that chemokine receptor-expressing tumors can be successfully controlled by delivering toxins through their chemokine receptors, we have generated fusion proteins designated chemotoxins: chemokines fused with toxic moieties that are nontoxic unless delivered into the cell cytosol. We demonstrate that chemokines fused with human RNase eosinophil-derived neurotoxin or with a truncated fragment of Pseudomonas exotoxin 38 are able to specifically kill tumors in vitro upon internalization through their respective chemokine receptors. Moreover, treatment with the thymus and activation-regulated chemokine (CCL17)-expressing chemotoxin efficiently eradicated CCR4-expressing cutaneous T cell lymphoma/leukemia established in NOD-SCID mice. Taken together, this work represents a novel concept that may allow control of growth and dissemination of tumors that use chemokine receptors to metastasize and circumvent immunosurveillance.
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PMID:CCR4-expressing T cell tumors can be specifically controlled via delivery of toxins to chemokine receptors. 1764 Oct 67

Acute graft-versus-host disease (GVHD) and leukemic relapse are serious complications of allogeneic stem-cell transplantation (SCT). Recruitment of activated T cells to host target tissues or sites of leukemic infiltration (graft-versus-leukemia [GVL]) is likely mediated by chemokine receptor-ligand interactions. We examined the contribution of donor cell CCR1 expression to the development of GVHD and GVL using a well-established murine SCT model (B6 --> B6D2F1) and CCR1-deficient mice (CCR1(-/-)). Allo-SCT with CCR1(-/-) donor cells significantly reduced systemic and target organ GVHD severity, and CCR1 expression on both T cells and accessory cells contributed to GVHD mortality. Significant GVL activity was preserved following CCR1(-/-) SCT, but the survival advantage diminished with increasing tumor burden. We then explored the effects of CCR1 expression on allo-specific T-cell responses. Although cytolytic effector function was maintained on a per-cell basis, T-cell proliferation and IFNgamma secretion were significantly reduced both in vivo and in vitro. T-cell function was partially dependent on interactions between CCR1 and CCL5. Collectively, these data demonstrate that CCR1 expression on donor cells contributes to the development of both GVHD and GVL, and suggest that CCR1/CCL5 receptor-ligand interactions modulate allo-specific T-cell responses occurring in this context.
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PMID:CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation. 1764 Dec 5

T-cell large granular lymphocyte (T-LGL) leukemia and chronic natural killer (NK) cell lymphocytosis (CNKL) are major subtypes of lymphoproliferative disease of granular lymphocytes (LDGL). To clarify the mechanism of LGL proliferation and the relationship with the chemokine system in LDGL, we enrolled 22 T-LGL leukemia patients and 8 CNKL cases, analyzed the expression profiles of chemokine receptors, and measured the serum concentrations of the corresponding chemokines. There were no significant differences in chemokine receptor expression profiles between T-LGL leukemia patients and healthy donors. An association of CCR5 and CXCR3 expression levels on LGLs was recognized in T-LGL leukemia patients (r = 0.84; P < .001). Among the chemokines, serum IP-10 and MIG levels were significantly higher in LDGL patients than in healthy donors (P < .05, and P < .001, respectively), and MIG expression was associated with the number of circulating LGLs (r = 0.73; P < .01). The chemokine receptor phenotypes of LDGL cells are essentially similar to those of normal T-cells and NK cells. The roles of IP-10 and MIG in the pathophysiology of LDGL need further examination.
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PMID:Close resemblance between chemokine receptor expression profiles of lymphoproliferative disease of granular lymphocytes and their normal counterparts in association with elevated serum concentrations of IP-10 and MIG. 1787 34

Stem cell research is currently focused on totipotent stem cells and their therapeutic potential, however adult stem cells, while restricted to differentiation within their tissue or origin, also have therapeutic utility. Transplantation with bone marrow hematopoietic stem cells (HSC) has been used for curative therapy for decades. More recently, alternative sources of HSC, particularly those induced to exit marrow or mobilize to peripheral blood by G-CSF, have become the most widely used hematopoietic graft and show significant superiority to marrow HSC. The chemokine/chemokine receptor axis also mobilizes HSC that occurs more rapidly than with G-CSF. In mice, the HSC and progenitor cells (HPC) mobilized by the CXCR2 receptor agonist GRObeta can be harvested within minutes of administration and show significantly lower levels of apoptosis, enhanced homing to marrow, expression of more activated integrin receptors and superior repopulation kinetics and more competitive engraftment than the equivalent cells mobilized by G-CSF. These characteristics suggest that chemokine axis-mobilized HSC represent a population of adult stem cells distinct from those mobilized by G-CSF, with superior therapeutic potential. It remains to be determined if the chemokine mobilization axis can be harnessed to mobilize other populations of unique adult stem cells with clinical utility.
Leukemia 2008 Mar
PMID:Chemokine-mobilized adult stem cells; defining a better hematopoietic graft. 1797 41

Almost 30 years have passed since adult T-cell leukemia (ATL) was identified as a new disease entity in Japan. During this period, its causative agent, human T-cell leukemia virus (HTLV-1), was discovered, and a crucial role of the viral product Tax in ATL leukemogenesis was demonstrated. Recently, another HTLV-1 product, HBZ, which is encoded on the negative strand, was found, and it has now become a subject of intensive research because of its possible activity in cell proliferation. It is, however, impossible to elucidate the whole process of ATL leukemogenesis by studying only HTLV-1, and aberrations of cellular genes such as tumor suppressor genes are also profoundly involved in the later stages of ATL development. In contrast with the progress in the understanding of ATL pathogenesis, more progress in developing therapy for ATL is needed, and there has been only slight improvement in the prognosis. Recently, unique therapeutic approaches targeting molecules and/or mechanisms involved in the pathogenesis have been explored, and some of them produced encouraging results that might lead to breakthrough therapies. One of these approaches, the use of monoclonal antibody against chemokine receptor CCR4, is now ongoing as a multicenter clinical trial in Japan. Here we review the state of the art regarding our understanding of ATL leukemogenesis and new potential molecular targets in ATL therapy.
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PMID:The state of the art in the pathogenesis of ATL and new potential targets associated with HTLV-1 and ATL. 1802

The World Health Organization classification of mature T-cell lymphoproliferative disorders, combines clinical, morphological and immunophenotypic data. The latter is a major contributor to the classification, as well as to the understanding of the malignant T-cell behavior. The fact that T-cell migration is regulated by chemokines should, in theory, enable us to identify tissue tropism and organ involvement by neoplastic T-cells by monitoring chemokine receptor surface expression. To address this issue we compared the expression of several early and late inflammatory, homeostatic, and organ specific chemokine receptors on blood T-cells from normal individuals and patients with T-cell large granular lymphocytic leukemia and peripheral T-cell lymphoma. T-cell large granular lymphocytic leukemia cells mainly express late inflammatory chemokine receptors (CXCR1 and CXCR2), whereas peripheral T-cell lymphoma cells usually express one or more organ homing receptors (CCR4, CCR6 and CCR7). Nevertheless, no clear correlation was found between CCR4 and CCR7 expression and skin and lymph node involvement, respectively. Compared to their normal counterparts, lymphoma T-cells displayed an exaggerated CCR4 expression, whereas leukemic T-cells had abnormally high CXCR1 and CXCR2 expression. Further analysis revealed that, in leukemia patients, the percentage of neoplastic cells expressing CCR5 correlates directly with lymphocytosis. In addition, in the case of CD8 T-cell leukemia patients, an inverse correlation with neutropenia was found. In lymphoma patients, higher CCR4 and CCR7 expression is accompanied by lower to absent CCR5 expression.
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PMID:Chemokine receptor repertoire reflects mature T-cell lymphoproliferative disorder clinical presentation. 1884 29

Host dendritic cells (DCs) play a critical role in initiating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL), and separation of GVL from GVHD remains a major challenge in the treatment of hematologic malignancies by allogeneic hematopoietic cell transplantation (HCT). Here, we show that preconditioning with anti-CD3 monoclonal antibody before conditioning with total body irradiation (TBI) prevents GVHD but retains GVL in a HCT model of major histocompatibility complex (MHC)-mismatched C57BL/6 donor to BALB/c host. Prevention of GVHD is associated with inhibition of donor T-cell expression of homing and chemokine receptors, and inhibition of GVHD target tissue expression of chemokines. Furthermore, inhibition of donor T-cell expression of gut homing alpha4beta7 and chemokine receptor (CCR)9 by anti-CD3 preconditioning results from a reduction of CD103(+) DCs in draining mesenteric lymph nodes (LNs), which is associated with down-regulation of DC expression of CCR7, a receptor required for tissue DC migration to draining LNs. These results indicate that anti-CD3 preconditioning reduces not only tissue release of chemokines but also prevents tissue DC migration to draining LNs and subsequently reduces the capacity of DCs of draining LNs to imprint donor T-cell tissue tropism. Therefore, modulation of host DCs by anti-CD3 preconditioning before HCT represents a new approach for separating GVL from GVHD.
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PMID:Anti-CD3 preconditioning separates GVL from GVHD via modulating host dendritic cell and donor T-cell migration in recipients conditioned with TBI. 1892 52

Hematopoietic and epithelial cancer cells express CXCR4, a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the bone marrow microenvironment constitutively secrete stromal cell-derived factor-1 (SDF-1/CXCL12), the ligand for CXCR4. Activation of CXCR4 induces leukemia cell trafficking and homing to the marrow microenvironment, where CXCL12 retains leukemia cells in close contact with marrow stromal cells that provide growth and drug resistance signals. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogs, can disrupt adhesive tumor-stroma interactions and mobilize leukemia cells from their protective stromal microenvironment, making them more accessible to conventional drugs. Therefore, targeting the CXCR4-CXCL12 axis is a novel, attractive therapeutic approach that is explored in ongoing clinical trials in leukemia patients. Initially, CXCR4 antagonists were developed for the treatment of HIV, where CXCR4 functions as a co-receptor for virus entry into T cells. Subsequently, CXCR4 antagonists were noticed to induce leukocytosis, and are currently used clinically for mobilization of hematopoietic stem cells. However, because CXCR4 plays a key role in cross-talk between leukemia cells (and a variety of other tumor cells) and their microenvironment, cancer treatment may become the ultimate application of CXCR4 antagonists. Here, we summarize the development of CXCR4 antagonists and their preclinical and clinical activities, focusing on leukemia and other cancers.
Leukemia 2009 Jan
PMID:CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. 1898 63


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