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)

Chronic myeloid leukemia cells contain a constitutively active Bcr-Abl tyrosine kinase, the target protein of Gleevec (STI571) phenylaminopyrimidine class protein kinase inhibitor. Here we provide evidence for metabolic phenotypic changes in cultured K562 human myeloid blast cells after treatment with increasing doses of STI571 using [1,2-13C2]glucose as the single tracer and biological mass spectrometry. In response to 0.68 and 6.8 microm STI571, proliferation of Bcr-Abl-positive K562 cells showed a 57% and 74% decrease, respectively, whereas glucose label incorporation into RNA decreased by 13.4% and 30.1%, respectively, through direct glucose oxidation, as indicated by the decrease in the m1/Sigma(m)n ratio in RNA. Based on the in vitro proliferation data, the IC50 of STI571 in K562 cultures is 0.56 microm. The decrease in 13C label incorporation into RNA ribose was accompanied by a significant fall in hexokinase and glucose-6-phosphate 1-dehydrogenase activities. The activity of transketolase, the enzyme responsible for nonoxidative ribose synthesis in the pentose cycle, was less affected, and there was a relative increase in glucose carbon incorporation into RNA through nonoxidative synthesis as indicated by the increase in the m2/Sigma(m)n ratio in RNA. The restricted use of glucose carbons for de novo nucleic acid and fatty acid synthesis by altering metabolic enzyme activities and pathway carbon flux of the pentose cycle constitutes the underlying mechanism by which STI571 inhibits leukemia cell glucose substrate utilization and growth. The administration of specific hexokinase/glucose-6-phosphate 1-dehydrogenase inhibitor anti-metabolite substrates or competitive enzyme inhibitor compounds, alone or in combination, should be explored for the treatment of STI571-resistant advanced leukemias as well as that of Bcr-Abl-negative human malignancies.
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PMID:Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells. 1148 2

The tyrosine kinase inhibitor imatinib (STI571, Glivec) blocks the activity of the BCR/ABL oncogene and induces hematologic remissions in the majority of patients with chronic myeloid leukemia (CML). Glivec is an aminopyrimidine derivative that interacts with the ATP-binding site within the kinase domain of ABL and several other tyrosine kinases, including c-KIT, PDGF beta receptor, and ARG. The compound is currently in phase III clinical trials. Although patients with chronic phase CML have been found to develop drug resistance only rarely so far, patients in more advanced phases of the leukemia develop resistance frequently. The available information on Glivec resistance will be reviewed.
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PMID:Mechanisms of resistance imatinib (STI571) in preclinical models and in leukemia patients. 1151 49

The tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) blocks the constitutively activated Bcr-Abl tyrosine kinase that is characteristic of chronic myeloid leukemia (CML). Molecular analysis for the presence of residual Bcr-Abl-positive cells in patients with a cytogenetic response following treatment with imatinib mesylate reveals that some patients have undetectable disease using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assays capable of detecting 1 in 10(5) Philadelphia chromosome-positive (Ph(+)) cells. To examine whether the leukemia is still Bcr-Abl-dependent in patients who have responded to imatinib mesylate but have relapsed, a quantitative assay that directly measures enzymatic activity of Bcr-Abl toward one of its major signaling substrates has been developed. This assay allows monitoring both of the imatinib mesylate sensitivity of patient cells in vitro, and of the endogenous inhibition of Bcr-Abl kinase activity during imatinib mesylate treatment and relapse. Studies show that imatinib mesylate resistance is associated with restored activation of the Bcr-Abl signal transduction pathway in the majority of cases, indicating that Bcr-Abl remains a valid target for therapeutic intervention. Understanding resistance mechanisms of Ph(+) leukemia to imatinib mesylate will allow design of therapies to overcome such barriers to efficacy.
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PMID:Molecular studies in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. 1152 97

Imatinib mesylate, also known as STI571 or CGP57148, is a competitive inhibitor of a few tyrosine kinases, including BCR-ABL, ABL, KIT, and the platelet-derived growth factor receptors (PDGF-R). It binds to the ATP-binding site of the target kinase and prevents the transfer of phosphate from ATP to the tyrosine residues of various substrates. At oral doses of 300 mg or greater, the vast majority of patients with chronic myeloid leukaemia achieve a haematological response and this is usually associated with limited toxicity. Imatinib also has substantial activity in Philadelphia chromosome-positive acute lymphoblastic leukaemia expressing the BCR-ABL fusion protein. Gastrointestinal stromal tumours (GISTs) have also been evaluated for clinical activity of imatinib. About 90% of malignant GISTs harbour a mutation in c-kit leading to KIT receptor autophosphorylation and ligand-independent activation. According to initial clinical studies, more than 50% of GISTs respond to therapy within a few months, and only about 10-15% progress. The potential for cure and the optimal length of treatment are currently not known. Several other human cancers may over-express KIT or PDGF-R, and clinical trials to evaluate the role of imatinib in the treatment of such cancers are currently ongoing. Imatinib is an example of a specifically designed, highly targeted cancer therapy, which poses novel requirements for both pathology laboratories and clinicians in terms of identifying the major molecular mechanisms involved in tumour growth.
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PMID:Tyrosine kinase inhibitor imatinib (STI571) as an anticancer agent for solid tumours. 1168 Jul 92

Novartis has launched imatinib, an inhibitor of tyrosine kinases, including Bcr-Abl, for the treatment of chronic myeloid leukemia (CML). Imatinib selectively inhibits activation of target proteins involved in cellular proliferation. It also inhibits c-KIT tyrosine kinase activity and is equally effective against both wild-type and constitutively active enzyme. Close correlation between in vitro responses to IFNalpha and imatinib suggested that it may be an alternative to IFNalpha therapy for chronic-phase CML, and the compound has the advantage that it can be administered orally. Futhermore, Bcr-Abl-expressing cells treated with imatinib undergo apoptosis. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. In February 2002, the FDA approved imatinib for the treatment of inoperable and/or metastatic malignant gastrointestinal stromal tumors (GIST); in September 2001, launch for the indication was expected in 2002. In November 2000, imatinib was granted Orphan Drug status in Japan for the target indication of Philadelphia chromosome-positive leukemia. By May 2001, imatinib had entered phase II trials for small cell lung cancer, prostate cancer and glioma. Imatinib has been launched in more than 35 countries, including the US, Brazil, Switzerland, Australia and the UK. By December 2001, the drug had also been launched in Japan. The drug is marketed as Gleevec (imatinib mesilate) in the US, and Glivec (imatinib) outside the US. In August 2001, Deutsche Bank estimated sales of SFr 233 million in 2001, rising to SFr 850 million in 2005; while Bear Stearns & Co predicted sales of SFr 250 million in 2001, rising to SFr 800 million in 2005.
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PMID:Imatinib. Novartis. 1205 2

Clinical phase I/II studies with the Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec, formerly STI571) for the treatment for chronic myelogenous leukemia (CML) demonstrated the safety and the remarkable efficacy of this molecularly targeted agent. However, a significant proportion of patients treated in the chronic phase of the disease after having failed interferon alpha (IFN) remain predominantly Philadelphia chromosome positive (Ph(+)), suggesting a risk of later relapses. Furthermore, results in blast crisis patients revealed a high frequency of relapses or resistance to imatinib. To circumvent resistance, improve response rates, or prolong survival, pre-clinical evaluations of combinations of imatinib with other agents have been pursued. Some of these have already been translated into clinical studies. Here, we first summarize evidence from pre-clinical studies on new combination regimens with imatinib in the treatment of CML. Second, we analyze preliminary clinical data of ongoing combination studies. Finally, we provide a summary of approaches that use novel antileukemic agents with molecularly characterized modes of action.
Leukemia 2002 Jul
PMID:Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective. 1209 45

BCR/ABL fusion tyrosine kinase is responsible for the initiation and maintenance of the Philadelphia chromosome (Ph(1))-positive chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemias (ALL). STI571 (Gleevec), a novel anti-leukemia drug targeting BCR/ABL kinase can induce remissions of the Ph(1)-positive leukemias. STI571 was recently combined with the standard cytostatic drugs to achieve better therapeutic results and to overcome emerging drug resistance mechanisms. We decided to search for a more specific partner compound for STI571. Our previous studies showed that a signaling protein phosphatidylinositol-3 kinase (PI-3k) is essential for the growth of CML cells, but not of normal hematopoietic cells (Blood, 86:726,1995). Therefore the anti- Ph(1)-leukemia effect of the combination of BCR/ABL kinase inhibitor STI571 and PI-3k inhibitor wortmannin (WT) or LY294002 (LY) was tested. We showed that STI571+WT exerted a synergistic effect against the Ph(1)-positive cell lines, but did not affect the growth of Ph(1)-negative cell line. Moreover, the combinations of STI571+WT or STI571+LY were effective in the inhibition of clonogenic growth of CML-chronic phase and CML-blast crisis patient cells, while sparing normal bone marrow cells. Single colony RT-PCR assay showed that colonies arising from the mixture of CML cells and normal bone marrow cells after treatment with STI571+WT were selectively depleted of BCR/ABL-positive cells. Biochemical analysis of the CML cells after the treatment revealed that combination of STI571+WT caused a more pronounced activation of caspase-3 and induced massive apoptosis, in comparison to STI571 and WT alone. In conclusion, combination of STI571+WT or STI571+LY may represent a novel approach against the Ph(1)-positive leukemias.
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PMID:Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. 1218 86

Chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemias arise from the genetic reciprocal translocation t(9;22), forming the BCR-ABL fusion gene. These lead to the expression of the constitutively active tyrosine kinase BCR-ABL, which is the causative oncogene for these leukemias. Allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT) is currently considered the only curative treatment for chronic myeloid leukemia (CML). Recently, the selective tyrosine kinase inhibitor imatinib mesylate (Glivec, formerly STI-571) has been shown to induce durable hematologic and major cytogenetic responses in a high percentage of patients with chronic phase CML. In patients with advanced disease remissions are transient and most patients relapse despite continued imatinib treatment. Some of these patients go on to receive allogeneic BMT or SCT, during which administration of imatinib is usually discontinued as it is believed to interfere with bone marrow engraftment. In this study, we examined the effect of imatinib on hematopoietic engraftment in a syngeneic mouse model. We found that imatinib has no significant influence on hematopoietic recovery in lethally irradiated mice in vivo. Thus, our results suggest that continued administration of imatinib in the course of BMT or SCT may be a feasible therapeutic regimen.
Leukemia 2002 Sep
PMID:Effects of imatinib on bone marrow engraftment in syngeneic mice. 1220 Jun 67

Bcr-Abl tyrosine kinase has been validated as a molecular target for the treatment of chronic myelogenous leukemia (CML). More recently, it has been reported that CML patients could develop resistance to the Bcr-Abl tyrosine kinase inhibitor, imatinib (STI571, Gleevec), pointing to the need for development of additional Bcr-Abl tyrosine kinase inhibitors or other therapeutic strategies. It was also found that a significant proportion of patients who received the Bcr-Abl inhibitor did not achieve complete cytogenetic response. Mechanisms for incomplete cytogenetic response to Bcr-Abl inhibition are not entirely clear. We report here three new pyrido[2,3-d]pyrimidine Bcr-Abl tyrosine kinase inhibitors, PD164199, PD173952, PD173958, that induced apoptosis of Bcr-Abl-dependent hematopoietic cells. An interleukin-3 (IL-3) autocrine loop was observed previously in primitive CD34(+)/Bcr-Abl(+) leukemic cells in CML patients. Using 32Dp210(Bcr-Abl)and Baf3p210(Bcr-Abl) cells as models, we tested whether IL-3 might protect Bcr-Abltransformed, IL-3-responsive cells from apoptosis caused by Bcr-Abl tyrosine kinase inhibition. Results of trypan blue exclusion, fluoroisothiocyanate-valyl-alanyl-aspartyl-[O-methyl] -fluoromethylketone (FITC-VAD-FMK), and Annexin-V/7-amino-actinomycin D (7-AAD) binding assays indicate that IL-3 could protect Bcr-Abl-transformed, IL-3 responsive hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors. This finding raises the possibility that the IL-3 autocrine loop found in primitive CD34(+)/Bcr-Abl(+) cells in CML patients could contribute to the incomplete eradication of Bcr-Abl(+) cells by Bcr-Abl inhibition.
Leukemia 2002 Sep
PMID:Interleukin-3 protects Bcr-Abl-transformed hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors. 1220 Jun 68

The long-term effort in investigating chemical methods to eliminate only cancer cells has improved our knowledge and has led to the development of new drugs. The targets for cancer treatment may be large polymeric molecules such as DNA or microtubules as well as regulatory pathways for tumor development and cell survival preservation or tyrosine kinase activity. Examples of new agents are: trastuzumab (Herceptin), a humanized monoclonal antibody that blocks the HER-2/neu proto-oncogene in combination with cytotoxic agents, is used in a percentage of breast cancer patients; signal transduction inhibitor of abl tyrosine kinase STI 571 (Glivec) has been shown to be an active treatment for chronic myeloid leukemia and GISTs; epidermal growth factor receptors in certain tumors have been targeted with agents such as C225 (Cetuximab) and ZD 1839 (IRESSA); an adenosine deaminase analogue of deoxyadenosine, Cladribine (2-chloro-2 deoxy-adenosine) has shown high effectiveness in hairy-cell leukemia and the multitargeted antifolate (Premetrexed) and several vaccines have been studied and are in clinical trials for resistant cancers. These new drug developments represent a promising field for future cancer management.
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PMID:Molecular characterization as a target for cancer therapy in relation to orphan status disorders (Review). 1237 30


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