Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Farnesyltransferase inhibitors represent a new class of agents that target signal transduction pathways responsible for the proliferation and survival of diverse malignant cell types. Although these agents were developed to prevent a processing step necessary for membrane attachment and maturation of Ras proteins, recent studies suggest that farnesyltransferase inhibitors block the farnesylation of additional cellular polypeptides, thereby exerting antitumor effects independent of the presence of activating ras gene mutations. Clinical trials of two farnesyltransferase inhibitors--the tricyclic SCH66336 and the methylquinolone R115777--as single agents have demonstrated disease stabilization or objective responses in 10 to 15% of patients with refractory malignancies. Combinations of farnesyltransferase inhibitors with cytotoxic chemotherapies are yielding complete and partial responses in patients with advanced solid tumors. A phase I trial of R115777 in refractory and relapsed acute leukemias induced responses in 8 (32%) of 25 patients with acute myelogenous leukemia (including two complete remissions) and in two of three with chronic myelogenous leukemia in blast crisis. In patients with solid tumors, accessible normal tissues such as peripheral blood lymphocytes or, perhaps more germane to epithelial malignancies, buccal mucosa have provided surrogate tissues that allow confirmation that farnesyltransferase is inhibited in vivo at clinically achievable drug doses. In conjunction with the R115777 acute leukemia trial, serial measurements provided evidence of farnesyltransferase enzyme inhibition, interference with farnesyltransferase function ( ie, protein processing), and blockade of signal transduction pathways in leukemic bone marrow cells. Preclinical studies of farnesyltransferase inhibitor resistance and clinical trials of farnesyltransferase inhibitors in combination with other agents currently are in progress.
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PMID:Current status of clinical trials of farnesyltransferase inhibitors. 1167 87

Despite major recent advances in the understanding of the molecular biology of the disease, the treatment of acute myeloid leukemia (AML) in adults remains challenging. For the 75% of AML patients older than 60 years, currently available treatments produce significant toxicity with poor overall response rates and survival. In younger patients, standard regimens using cytarabine and an anthracycline for induction followed by some form of intensive postremission therapy can produce response rates of 70% with 5-year relapse-free survival rates of 25% to 40%. Chromosomal analyses define three prognostic categories with favorable, intermediate, and unfavorable risk. In older adults, AML appears to be an intrinsically resistant disorder of proximal pluripotent hematopoietic stem cells. A variety of targeted therapies currently in development include modulators of MDR1-mediated drug resistance, immunotherapeutics, angiogenesis inhibitors, proapoptotic antisense oligonucleotides, and specific small molecule inhibitors of tyrosine kinase and farnesyltransferase. For example, oral farnesyltransferase inhibitors have demonstrated activity and tolerability in patients with refractory AML and are now in phase II testing. Such targeted therapeutics offer the promise of novel antileukemic activity combined with an improved therapeutic index.
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PMID:Treatment of acute myeloid leukemia: state-of-the-art and future directions. 1221 87

Acute leukemia carries a poor prognosis, especially in older patients, emphasizing the need for novel therapies. Reasons for treatment failure include high rates of relapse and treatment-related toxicities. Farnesyltransferase inhibitors (FTIs), a new class of agents that can interfere with intracellular signaling, are good therapeutic candidates for study in these diseases, given the relatively high levels of the target enzyme, farnesyltransferase, expressed in bone marrow and by peripheral circulating lymphocytes. ZARNESTRA (formerly R115777, Ortho Biotech Oncology, Raritan, NJ) is an FTI that has clinical activity in solid tumors and antileukemic activity in vitro. In a phase I trial of Zarnestra in patients with high-risk leukemia (resistant or relapsed acute myeloid leukemia [AML] or acute lymphocytic leukemia [ALL], chronic myeloid leukemia [CML] in blast crisis, or AML in poor prognosis subgroups), patients experienced an overall response rate of 29%. Zarnestra was well tolerated with no dose-limiting toxicities through doses up to 900 mg twice daily. Assays measuring inhibition of farnesyltransferase activity showed a reliable inhibition at doses greater than 300 mg twice daily, and pharmacokinetic studies indicated that Zarnestra accumulated preferentially in the bone marrow in a dose-dependent fashion. These results suggest that Zarnestra should be studied further in patients with myeloid leukemia.
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PMID:Farnesyltransferase inhibitors and myeloid malignancies: phase I evidence of Zarnestra activity in high-risk leukemias. 1221 91

Childhood acute myeloid leukemia is a heterogeneous group of disorders that remains challenging to treat. There are multiple common genetic alterations in childhood acute myeloid leukemia. These include chromosomal translocations affecting RUNX1-CBFbeta, RARalpha, and MLL. There are known activating mutations in the genes for the receptor tyrosine kinases FLT3, KIT, and FMS. As these abnormalities are better understood, they are providing important insights into the pathogenesis of disease as well as information about prognosis. Although intensive chemotherapy remains the mainstay of acute myeloid leukemia therapy, long-term cure rates with chemotherapy alone remain approximately 50%, creating an urgent need for better therapies. Multiple avenues are being explored in the design of new treatments for pediatric acute myeloid leukemia. Targeted therapies include targeted antibody therapy; inhibitors of FLT3, KIT, and farnesyltransferase; diphtheria toxin conjugated to the granulocyte-macrophage colony-stimulating factor; and antisense oligonucleotides. Another area of interest is chromatin remodeling and differentiation therapy, including agents such as all- retinoic acid, arsenic trioxide, and inhibitors of DNA methylation and histone deacetylation. There are also ongoing trials of antiangiogenesis agents. Another avenue for novel therapies is immunotherapy with agents such as interleukin-2 and tumor vaccines. This article reviews recent advances in understanding of the molecular basis for childhood acute myeloid leukemia and the design of novel therapies for the treatment of childhood acute myeloid leukemia.
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PMID:Update in childhood acute myeloid leukemia: recent developments in the molecular basis of disease and novel therapies. 1248 9

R115777 is an orally bioavailable farnesyltransferase inhibitor (FTI) that has displayed encouraging activity in patients with acute myeloid leukemia. To determine whether R115777 might exert similar activity in myelofibrosis with myeloid metaplasia (MMM), we evaluated its effects on circulating myeloid progenitor cells from patients with MMM (n=25) using in vitro colony-forming assays. The median R115777 concentrations that inhibited colony formation by 50% were 34 and 2.7 nM for myeloid and megakaryocytic colonies from MMM patients, respectively. Progenitors from normal controls and patients with other myeloproliferative disorders demonstrated similar sensitivity. Since the ras polypeptides are one putative target of FTIs, the potential role of ras effectors was examined by incubating parallel progenitor assays with the phosphatidyl-inositol-3 (PI-3) kinase inhibitor LY294002 and the mitogen-activated protein kinase 1 inhibitor PD98059. MMM progenitor colonies (n=7) were highly sensitive to LY294002 but not to PD98059, implying that the PI-3 kinase pathway may be critical for survival and proliferation of these cells. In addition to indicating that MMM progenitors are sensitive to clinically achievable R115777 concentrations in vitro, these results provide a potential explanation for the thrombocytopenia observed with R115777 during the treatment of other hematologic malignancies.
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PMID:In vitro antiproliferative activity of the farnesyltransferase inhibitor R115777 in hematopoietic progenitors from patients with myelofibrosis with myeloid metaplasia. 1275 Jun 96

The WHO classification of adultory acute myeloid leukemia puts the main emphasis on prognosis, based mainly upon cytogenetic findings and gene-expression profiles. The complex prognostic assessment provides a more solid basis for early therapeutic stratification. This review focuses mainly on medical therapy. Induction phase is quite uniform, it consists of antracyclin and cytosin arabinosid. High-dose cytosin arabinosid is the predominant tool of postinduction therapy, especially in the favorable cytogenetic pattern cases. All-trans retinoic acid resulted in extremely good results in the promyelocytic cases, and this therapy seems to be advantageous in respect of acute DIC, too. Arsenic trioxide could be the drug of choice in relapsed promyelocytic leukemia. Some new agents are promising in refractory or relapsed cases, i.e. antibodies (Mylotarg) or farnesyltransferase inhibitors. The near future may bring about new therapeutic approaches, involving immunotherapy (dendritic cell vaccines) or gene-therapy as well.
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PMID:[Expanding possibilities, strategic considerations, and novel methods in the diagnosis and chemotherapy of adult acute myeloid leukemia]. 1457 74

The farnesyltransferase inhibitors (FTIs) were designed to inhibit the post-translational processing of Ras proteins, which are mutated in 30% of all human cancers. Recent studies suggest, however, that the target of FTIs may be a protein other than Ras, and that these agents may be more appropriately used to treat tumors with activated wild-type ras signaling. Preliminary results from several phase II and phase III studies have been reported. The FTIs fail to show significant single-agent activity in non-small cell lung cancer, small cell lung cancer, pancreatic cancer, refractory colorectal cancer, and bladder cancer. Activity has been shown in hematologic malignancies (acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome), breast cancer, and glioma. Several combination studies of FTIs and standard cytotoxic agents are ongoing.
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PMID:Farnesyltransferase inhibitors. 1498 78

Angiogenesis is defined as the formation of new capillaries from prexisting blood vessels and plays an important role in the progression of solid tumors and hematologic malignancies. Markers of angiogenesis correlate with clinical characteristics in leukemia and non-Hodgkin's-lymphoma, serving as predictors of poor prognosis. Antiangiogenic effects of chemotherapeutics as well as of novel drugs such as farnesyltransferase inhibitors and tyrosine kinase inhibitors such as Gleevec might contribute to their therapeutic potential. Thalidomide which has antiangiogenic effects and direct cytotoxic effects was found to be effective in multiple myeloma and is considered as an established treatment modality for patients with refractory or relapsed multiple myeloma. Thalidomide has a significant therapeutic effect in myelodysplastic syndrome (MDS) by improving cytopenia and achieving independence of transfusion therapy in a subset of patients. Preliminary data indicate activity of specific VEGF receptor tyrosine kinase (RTK) inhibitors in multiple myeloma (MM) and acute myeloid leukemia (AML). The positive correlation between increased levels of angiogenic cytokines and clinical response to VEGF-RTK inhibitors and thalidomide indicates the relevance of detecting angiogenesis markers to identify best candidate patients for specific approaches. Including antiangiogenic drugs into treatment protocols for hematologic malignancies is an important task for future clinical studies.
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PMID:Antiangiogenic therapy in hematologic malignancies. 1507 37

The incidence of the major clonal myeloid diseases, clonal cytopenias, acute, subacute (oligoblastic), and chronic myelogenous leukemia, polycythemia vera, thrombocythemia, and idiopathic myelofibrosis increases in a log-linear manner from young adulthood through advanced age. In older patients, diseases requiring cytotoxic treatment are more difficult and less successful to manage because comorbid conditions and poor performance status are more prevalent, decreasing the tolerance to therapy and increasing the frequency of side effects. This age effect is highlighted by the dramatically less favorable outcome in older than younger patients with acute myeloid leukemia with similar "favorable" cytogenetic changes. In addition, in acute and subacute myeloid leukemia in older patients, the disease is intrinsically more resistant to therapy. Overexpression of drug resistance genes and unfavorable genetic mutations are more prevalent in older patients and provide evidence that acute myeloid leukemia is often qualitatively different in these patients. The gradient of age effects is continuous; the frequency of poor outcome increasing by decade (or less). The decline in survival becomes especially steep as quinquagenarians (50-year-olds) age to nonagenarians (90-year-olds). Although improved drug schedules have led to significant improvements in event-free survival in younger patients, these improvements have been far less evident in older patients. New approaches, especially the development of drugs aimed at new targets, will be required to obtain a high frequency of long-term remissions in older patients. Agents that reverse inherent cellular drug resistance, farnesyltransferase inhibitors, BCL-2 inhibitors, and FLT3 inhibitors are early examples of such approaches.
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PMID:The relationship of patient age to the pathobiology of the clonal myeloid diseases. 1511 49

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


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