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), a selective inhibitor of BCR-ABL tyrosine kinase, has shown excellent efficacy in patients with chronic myelogenous leukemia (CML) in the chronic phase, however, it does not in those in the accelerated phase or blastic crisis. In patients with CML who have undergone allogeneic stem cell transplantation, imatinib has the capability to induce hematological and even molecular response, and provides a prolonged survival among those in the chronic and accelerated phases. It has been demonstrated that major cytogenic response is a surrogate marker for survival in cases receiving imatinib. It has also been demonstrated that a genome-wide cDNA microarray enables the prediction of sensitivity to imatinib. The acquired resistance in patients who failed to respond to imatinib seemed to be induced by several point mutations in the BCR-ABL gene, which were likely to affect the binding of imatinib with BCR-ABL. Polyclonal cells which harbor distinct mutations in a single patient seemed to be selected in vivo under the selective pressure of imatinib, indicating the rationale of combined treatment with other types of agents. Recently, SPIRIT (STI571 Prospective International Randomized Trials) have been conducted, in which the efficacy of imatinib monotherapy, and imatinib combined with interferon or cytarabine were compared. New agents which inhibit the signaling pathway related to BCR-ABL, such as adaphostin (NSC680410), farnesyltransferase inhibitor SCH66336, MAP kinase inhibitor PD184352, PD98059, U0126, and antibiotic geldanamycin, have shown excellent activity combined with imatinib in vitro.
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PMID:[Imatinib therapy for patients with chronic myelogenous leukemia]. 1528 51

The treatment of hematologic malignancies has progressed in the last few years. Identification of new pathways and target molecules in leukemia has ushered in a promising new era of therapy. Ras mutations have recently been implicated in the pathogenesis of acute leukemia, and inhibition of Ras signaling through the use of farnesyltransferase inhibitors (FTIs) has shown promise in early trials in acute myeloid leukemia (AML). Responses have not correlated with the presence of Ras mutations, suggesting that novel pathways are involved. In several early trials, FTIs have shown activity as single agents in poor-risk AML, suggesting a potential role in combination with standard chemotherapy. FTIs are now being tested in other clinical settings, such as myelodysplasia, chronic myelogenous leukemia and multiple myeloma, with encouraging preliminary activity.
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PMID:Role of farnesyltransferase inhibitors in hematologic malignancies. 1548 18

Advances in molecular biology and genomics enabled more detailed view on the pathogenesis of myeloproliferative disorders, which are considered to be a diseases of hematopoietic stem cell. The autor provides an brief overview of the genetic alterations, leading to the chronic myeloid leukemia, myelodysplastic syndrome and acute myeloid leukemia. In the second part, molecular targeted therapies that have been developed based on these insights are reviewed. These are particularly methods preventing increased proliferation such as inhibition of tyrosinkinases (imatinib, dasatinib), inhibitions of farnesyltransferase (tipifarnib), inhibition of angiogenesis (bevacizumab, vatalanib), induction of diferentiation (hypomethylating agenents) and induction of apoptosis (bortezomib). More detailed information is given on some novel drugs which are currently in clinical trials.
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PMID:[Some new findings in the pathogenesis of myeloproliferative disorders and new insight into more effective treatment]. 1646 34

Despite the progress made in the last decade in the treatment of haematological malignancies, most of the patients still have a dismal prognosis. However, the improved knowledge of tumour biology opened the possibility to develop new 'intelligent' therapeutic strategies, the so-named targeted therapies. These approaches aim to selectively kill cancer cells by basing this selectivity on both the expression of a specific molecule on their surface or the activation of particular molecular pathways secondary to malignant transformation. In this article, the authors review the main targeted therapies available in haematology, such as monoclonal antibodies, tyrosine kinase, farnesyltransferase, as well as proteasome inhibitors, antiangiogenesis compounds and antisense oligonuceotides. Finally, the authors focus on the application of imatinib mesylate in chronic myeloid leukaemia as the paradigm of molecular treatment. Although these novel therapies are beginning to fulfil their promise, continued research efforts are needed to determine the optimal role of these strategies in haemato-oncology.
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PMID:Advances in the treatment for haematological malignancies. 1655 88

Chronic myeloid leukemia (CML), a hematopoietic stem-cell disorder, cannot be eradicated by conventional chemotherapy or the tyrosine kinase inhibitor imatinib mesylate (IM). To target CML stem/progenitor cells, we investigated BMS-214662, a cytotoxic farnesyltransferase inhibitor, previously reported to kill nonproliferating tumor cells. IM or dasatinib alone reversibly arrested proliferation of CML stem/progenitor cells without inducing apoptosis. In contrast, BMS-214662, alone or in combination with IM or dasatinib, potently induced apoptosis of both proliferating and quiescent CML stem/progenitor cells with less than 1% recovery of Philadelphia-positive long-term culture-initiating cells. Normal stem/progenitor cells were relatively spared by BMS-214662, suggesting selectivity for leukemic stem/progenitor cells. The ability to induce selective apoptosis of leukemic stem/progenitor cells was unique to BMS-214662 and not seen with a structurally similar agent BMS-225975. BMS-214662 was cytotoxic against CML blast crisis stem/progenitor cells, particularly in combination with a tyrosine kinase inhibitor and equally effective in cell lines harboring wild-type vs mutant BCR-ABL, including the T315I mutation. This is the first report of an agent with activity in resistant and blast crisis CML that selectively kills CML stem/progenitor cells through apoptosis and offers potential for eradication of chronic phase CML.
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PMID:BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. 1815 96

We examined the involvement of sphingosine kinase-1 (SphK1), which governs the ceramide/sphingosine-1-phosphate balance, in susceptibility to imatinib of either sensitive or resistant chronic myeloid leukemia cells. Imatinib-sensitive LAMA84-s displayed marked SphK1 inhibition coupled with increased content of ceramide and decreased pro-survival sphingosine-1-phosphate. Conversely, no changes in the sphingolipid metabolism were observed in LAMA84-r treated with imatinib. Overcoming imatinib resistance in LAMA84-r with farnesyltransferase or MEK/ERK inhibitors as well as with cytosine arabinoside led to SphK1 inhibition. Overexpression of SphK1 in LAMA84-s cells impaired apoptosis and inhibited the effects of imatinib on caspase-3 activation, cytochrome c and Smac release from mitochondria through modulation of Bim, Bcl-xL and Mcl-1 expression. Pharmacological inhibition of SphK1 with F-12509a or its silencing by siRNA induced apoptosis of both imatinib-sensitive and -resistant cells, suggesting that SphK1 inhibition was critical for apoptosis signaling. We also show that imatinib-sensitive and -resistant primary cells from chronic myeloid leukemia patients can be successfully killed in vitro by the F-12509a inhibitor. These results uncover the involvement of SphK1 in regulating imatinib-induced apoptosis and establish that SphK1 is a downstream effector of the Bcr-Abl/Ras/ERK pathway inhibited by imatinib but upstream regulator of Bcl-2 family members.
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PMID:Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells. 1840 14

Increased understanding of the cellular mechanisms associated with various malignancies has allowed researchers to develop agents that selectively target the cellular proteins and pathways implicated in the pathogenesis of malignancy. Tipifarnib is a specific and potent farnesyltransferase inhibitor that demonstrates in vivo and in vitro activity against a variety of human cancers. Although tipifarnib was initially thought to target the Ras protein, recent evidence suggests that the presence of ras mutations is not necessary for the antitumor effects of tipifarnib, and that tipifarnib may exert its effects downstream of Ras. The oral administration and favorable toxicity profile of tipifarnib, combined with its activity in a variety of intracellular pathways that have been implicated in the pathogenesis of hematologic malignancies, make it an especially attractive agent for use in patients with acute myeloid leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia (CML), and multiple myeloma. Because hematologic malignancies are likely driven by multiple genetic aberrations, the most effective treatment strategy will likely combine multiple agents with complementary mechanisms of action. Thus, additional studies of combination regimens that incorporate tipifarnib with other antineoplastic agents are crucial. Early results from studies combining tipifarnib with imatinib or etoposide in CML and AML have been promising and warrant further evaluation in larger clinical trials.
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PMID:Farnesyltransferase inhibition in hematologic malignancies: the clinical experience with tipifarnib. 1849 98

BCR-ABL is a causative tyrosine kinase (TK) of chronic myelogenous leukemia (CML). In CML patients, although myeloid cells are remarkably proliferating, erythroid cells are rather decreased and anemia is commonly observed. This phenotype is quite different from that observed in polycythemia vera (PV) caused by JAK2 V617F, whereas both oncogenic TKs activate common downstream molecules at the level of hematopoietic stem cells (HSCs). To clarify this mechanism, we investigated the effects of BCR-ABL and JAK2 V617F on erythropoiesis. Enforced expression of BCR-ABL but not of JAK2 V617F in murine LSK (Lineage(-)Sca-1(hi)CD117(hi)) cells inhibited the development of erythroid cells. Among several signaling molecules downstream of BCR-ABL, an active mutant of N-Ras (N-RasE12) but not of STAT5 or phosphatidylinositol 3-kinase (PI3-K) inhibited erythropoiesis, while N-RasE12 enhanced the development of myeloid cells. BCR-ABL activated Ras signal more intensely than JAK2 V617F, and inhibition of Ras by manumycin A, a farnesyltransferase inhibitor, ameliorated erythroid colony formation of CML cells. As for the mechanisms of Ras-induced suppression of erythropoiesis, we found that GATA-1, an erythroid-specific transcription factor, blocked Ras-mediated mitogenic signaling at the level of MEK through the direct interaction. Furthermore, enforced expression of N-RasE12 in LSK cells derived from p53-, p16(INK4a)/p19(ARF)-, and p21(CIP1/WAF1)-null/wild-type mice revealed that suppressed erythroid cell growth by N-RasE12 was restored only by p21(CIP1/WAF1) deficiency, indicating that a cyclin-dependent kinase (CDK) inhibitor, p21(CIP1/WAF1), plays crucial roles in Ras-induced suppression of erythropoiesis. These data would, at least partly, explain why respective oncogenic TKs cause different disease phenotypes.
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PMID:BCR-ABL but not JAK2 V617F inhibits erythropoiesis through the Ras signal by inducing p21CIP1/WAF1. 2066 70


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