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)

Knowledge of signal transduction pathways has uncovered therapeutic targets for cancer. Based on genetic and biochemical studies of leukemia cells, inhibiting hyperactive Ras represents a rational therapeutic strategy for many hematologic malignancies. Because posttranslational processing by farnesyltransferase is essential for transformation by oncogenic Ras, specific inhibitors of this enzyme are being evaluated as cancer therapeutics. The authors review recent laboratory insights on farnesyltransferase biology and on the development of inhibitors, summarize preclinical and clinical data in myeloid malignancies, and briefly discuss other strategies of interfering with hyperactive Ras.
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PMID:Ras processing as a therapeutic target in hematologic malignancies. 1204 5

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

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.
Leukemia 2003 May
PMID:In vitro antiproliferative activity of the farnesyltransferase inhibitor R115777 in hematopoietic progenitors from patients with myelofibrosis with myeloid metaplasia. 1275 Jun 96

Treatment of chronic myelogenous leukemia with a specific inhibitor of the Bcr/Abl tyrosine kinase, imatinib, has shown great promise. However, acute lymphoblastic leukemias that express Bcr/Abl only transiently respond to imatinib. Therefore, alternative treatments for this type of leukemia are urgently needed. Here, we examined the activity of the farnesyltransferase inhibitor SCH66336 as a single chemotherapeutic agent in a nude mouse model representative of very advanced stage Bcr/Abl P190-positive lymphoblastic leukemia/lymphoma. Our results show that oral administration of the inhibitor was able to significantly increase the survival of these mice compared to controls treated with vehicle (P<0.005), and caused marked regression of the tumor burden in the treated mice. Upon prolonged treatment, lymphomas re-emerged and a subset of cells from two of such lymphomas tested was able to survive in the presence of increased concentrations of SCH66336. The same cells, however, remained sensitive towards imatinib. A combination of the two drugs, preceded by a therapy to reduce the initial tumor burden, could be very effective in the treatment of Ph-positive ALL. We conclude that SCH66336, on its own, is remarkably effective in eradicating large numbers of lymphoblastic lymphoma cells and causing visible reduction in tumor size, with minimal toxicity.
Leukemia 2004 Jan
PMID:A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl. 1460 39

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 Ras pathway transduces divergent signals determining normal cell fate and is frequently activated in hematopoietic malignancies, but the manner in which activation contributes to human leukemia is poorly understood. We report that a high level of activated H-Ras signaling in transduced primary human hematopoietic progenitors reduced their proliferation and enhanced monocyte/macrophage differentiation. However, the exposure of these cells to a farnesyltransferase inhibitor and establishment of a moderate level of Ras activity showed increased proliferation, an elevated frequency of primitive blast-like cells, and progenitors with enhanced self-renewal capacity. These results suggest that the amplitude of Ras pathway signaling is a determinant of myeloid cell fate and that moderate Ras activation in primitive hematopoietic cells can be an early event in leukemogenesis.
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PMID:Hematopoietic cell fate and the initiation of leukemic properties in primitive primary human cells are influenced by Ras activity and farnesyltransferase inhibition. 1528

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

Interactions between the Chk1 inhibitor UCN-01 and the farnesyltransferase inhibitor L744832 were examined in human leukemia cells. Combined exposure of U937 cells to subtoxic concentrations of UCN-01 and L744832 resulted in a dramatic increase in mitochondrial dysfunction, apoptosis, and loss of clonogenicity. Similar interactions were noted in other leukemia cells (HL-60, Raji, Jurkat) and primary acute myeloid leukemia (AML) blasts. Coadministration of L744832 blocked UCN-01-mediated phosphorylation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), leading to down-regulation of phospho-cyclic adenosine monophosphate responsive element-binding protein (phospho-CREB) and -p90(RSK) and activation of p34(cdc2) and stress-activated protein kinase/ERK kinase/c-Jun N-terminal kinase (SEK/JNK). Combined treatment also resulted in pronounced reductions in levels of phospho-Akt, -glycogen synthase kinase-3 (-GSK-3), -p70(S6K), -mammalian target of rapamycin (-mTOR), -forkhead transcription factor (-FKHR), -caspase-9, and -Bad. Ectopic expression of Bcl-2 or Bcl-xL but not dominant-negative caspase-8 blocked UCN-01/L744832-mediated mitochondrial dysfunction and apoptosis but did not prevent activation of p34(cdc2) and JNK or inactivation of MEK/ERK and Akt. Enforced expression of myristoylated Akt but not constitutively active MEK significantly attenuated UCN-01/L744832-induced apoptosis. However, dual transfection with Akt and MEK resulted in further protection from UCN-01/L744832-mediated lethality. Finally, down-regulation of JNK1 by siRNA significantly reduced the lethality of the UCN-01/L744832 regimen. Together, these findings suggest that farnesyltransferase inhibitors interrupt the cytoprotective Akt and MAPK pathways while reciprocally activating SAPK/JNK in leukemia cells exposed to UCN-01 and, in so doing, dramatically increase mitochondria-dependent apoptosis.
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PMID:Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK. 1549 23

Juvenile myelomonocytic leukemia (JMML) is the most common myeloproliferative/myelodysplastic disorder seen in children. The treatment of choice, allogeneic stem cell transplantation, provides the only known cure for the disease, but relapse after transplant is common. The authors describe a 5-year-old boy diagnosed at age 34 months with JMML that evolved to acute myeloid leukemia. Initial treatment consisted of fludarabine and cis-retinoic acid therapy, followed by a matched sibling bone marrow transplant. After a relapse, he received a second transplant from the same donor, using peripheral blood stem cells, followed by repeated donor leukocyte infusions. After the second relapse, he received the farnesyltransferase inhibitor R115777 (tipifarnib, Zarnestra), but the leukemia persisted. When bone marrow blasts numbered 60% of the mononuclear cells, he received single-agent clofarabine induction (52 mg/m/d) for 5 days. After three courses, he attained a remission marrow with 5% blasts and disappearance of the 5q- and 9q- cytogenetic abnormalities.
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PMID:Complete remission following clofarabine treatment in refractory juvenile myelomonocytic leukemia. 1575 Apr 51

Resistance to cytotoxic drugs frequently emerges during treatment of leukemia with conventional chemotherapy. New classes of anticancer drugs, such as the farnesyltransferase inhibitors (FTIs), show therapeutic promise, but whether cells will easily develop resistance against them is not known. Here, we grew breakpoint cluster region/Abelson murine leukemia (Bcr/Abl) P190 lymphoblasts on stroma and made them resistant to the FTI SCH66336/lonafarnib to model emerging drug resistance in a patient. These cells exhibited greatly increased (> 100-fold) expression levels of a novel ATP (adenosine triphosphate)-binding cassette (ABC) transporter-homologous gene, ATP11A. We showed that overexpression of this gene provided protection against the effects of SCH66336, whereas knockdown of endogenous ATP11a using small interfering RNA (siRNA) made cells more sensitive to this drug. The lymphoblasts that were resistant to this FTI were also more resistant to FTI-276 and to GGTI-298, 2 other structurally similar inhibitors. Surprisingly, the cells were also able to survive higher concentrations of imatinib mesylate, the Bcr/Abl tyrosine kinase inhibitor. However, the cells remained sensitive to vincristine. Our results show that elevated levels of ATP11a can protect malignant lymphoblastic leukemia cells against several novel small molecule signal transduction inhibitors. A determination of the expression levels of this gene may have prognostic value when treatment with such classes of drugs is contemplated.
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PMID:Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a. 1586 Jun 63


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