Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myelogenous leukemia in more than 90% of patients is associated with the abnormal Philadelphia chromosome, which results in aberrant BCR-ABL chimeric gene expression. The mean overall survival on standard chemotherapy (which is not curative) ranges between 54-72 months. Selected patients with CML can be cured by allogeneic hemopoietic stem cell transplantation. Only 30% of patients has an optimal HLA-identical sibling donor. It is possible to find well-matched unrelated donor for another 20-30% of patients, however matched-unrelated donor transplantation is still associated with relative high risk of complications and cannot be used in elderly patients. Interferon alpha treatment in monotherapy or in combination with ARA-C can induce a cytogenetical and molecular remission in selected group of patients, which benefits with significantly prolonged survival. Nevertheless the cost of this treatment is high and long period of therapy is required to assess its efficacy. In patients lacking matched related or unrelated donors for allogeneic transplantation, autologous stem cell transplantation could be the alternative method of treatment. Discussed in the paper method of mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cells collected during early phase of bone marrow regeneration after "mobilizing" chemotherapy (mini-ICE) enables to achieve a complete or major cytogenetical response in about 77% of patients. There is only minimal morbidity and no transplant-related mortality. This procedure and the post-transplant immunotherapy (IFN alpha, interleukin-2) can considerably suppress the pathological clone and significantly prolong the overall survival in CML patients not eligible for allogeneic transplantation.
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PMID:[Autologous hemopoietic stem cell transplantation in treatment of chronic myelogenous leukemia]. 1049 85

Chronic myeloid leukemia (CML) is a hematological malignancy resulting from clonal expansion and massive accumulation of leukemic myeloid cells that retain differentiation and maturation capacity. Since CML cell accumulation has been related to apoptosis inhibition by the product of the BCR-ABL gene, attempts to eradicate leukemic cells would require therapeutic drugs able to overcome this inherent resistance. Here, we investigated in vitro the apoptotic effect of all-trans retinoic acid (ATRA) and cytosine arabinoside (ARA-C), employed alone, in combination or in sequence, on freshly isolated cells from 10 patients with chronic-phase CML. Our cell cultures showed that both ATRA and ARA-C were able to induce apoptosis in CML cells, even if ARA-C resulted more effective than ATRA. The combined use of ATRA and ARA-C seemed to have only an additive effect while the sequential use did not show any advantage. These in vitro observations indicate that ATRA and ARA-C may be effective in reducing CML cells through apoptosis induction, suggesting that it could be worthwhile to examine ATRA and ARA-C combinations in the therapy of CML.
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PMID:In vitro apoptotic response of freshly isolated chronic myeloid leukemia cells to all-trans retinoic acid and cytosine arabinoside. 1115 76

Cytoreductive therapy can ameliorate symptoms in chronic myeloid leukemia (CML) but only treatment beyond hematologic remission aiming to affect the leukemic clone can improve prognosis. Up to now bone marrow transplantation is the only established therapy with the potential to completely eliminate the BCR-ABL positive cell population. Interferon-alpha (IFN-alpha) as well as cytosine arabinoside (ARA-C), particularly in combination, have been shown to be effective in achieving cytogenetic remission in some patients. With Glivec (STI-571) there is now a drug available which can induce major cytogenetic response in more than half of the patients who have failed IFN-alpha treatment and thus possibly delay or prevent blast crisis. Recent reports, however, have shown that primitive, quiescent, Philadelphia-positive stem cells are insensitive to STI-571 in vitro. Such cells could be the basis of relapse after termination of Glivec-therapy.
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PMID:[Treatment of residual disease in chronic myeloid leukemia with STI-571 (Glivec)]. 1250 64

BCR/ABL positive cells are known to be resistant to DNA damage induced by chemotherapy while they are sensitive to imatinib (IM), a tyrosine kinase inhibitor (TKI). To evaluate whether this drug can increase the activity of cytotoxic drugs on BCR/ABL positive cells, we measured the toxicity of cytosine arabinoside (ARA-C), hydroxyurea (HU) and melphalan (MEL), after a pretreatment of 24 h with IM on K562 cell line. The highest cytotoxic effect was seen when the TKI was followed by MEL; our results indicate that inhibition of BCR/ABL activity by IM increased the cytotoxicity of MEL by favoring the DNA damage induced by this drug and by shortening the time for DNA repair at the G2/M checkpoint. A stronger activation of some genes involved in both intrinsic and extrinsic apoptotic pathways was also observed with IM/MEL combination compared to IM or MEL alone. The drugs association was further tested in a type of BaF3 cells (TonB.210) where the BCR-ABL expression is inducible by doxycycline; in this model it was confirmed that a reduction of BCR/ABL activity resulted in an increased susceptibility to the cytotoxic effect of MEL. Furthermore, we studied the effect of IM/MEL treatment on the proliferative potential of myeloid progenitors of six CML patients at diagnosis. The analysis of CFU-GM and BFU-E colonies demonstrated that the IM/MEL combination was more effective than IM alone in reducing the overall number of colonies and the number of copies of BCR/ABL. In conclusion, our work shows that inhibition of BCR/ABL activity increases the toxicity of MEL and allows an efficient killing of leukemic cells, suggesting that a clinical development of this approach could have therapeutic advantages for CML patients.
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PMID:Imatinib increases cytotoxicity of melphalan and their combination allows an efficient killing of chronic myeloid leukemia cells. 2119 61