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)

Action of N(epsilon)-(carboxymethyl)lysine (CML) adduct, an advanced glycation end product, was investigated on neovascularization of cultured choroidal explants in streptozotocin (STZ)-diabetic rat. The choroidal explants of early (4 weeks after an injection of 60 mg/kg STZ) and advanced (8 months after the STZ injection) diabetic rats, and age-matched normal rats were cultured in fibrin gel with Dulbecco's modified Eagle medium containing fetal bovine serum. The number of budded microvessel-like structures was counted and used as an index of in vitro neovascularization. Choroidal explants in the early diabetic stage released vascular endothelial growth factor (VEGF) and tended to increase tumor necrosis factor (TNF) alpha and platelet-derived growth factor (PDGF)-B, and concomitantly facilitated growth of sprout and buds, compared to the normal control. When choroidal explants were stimulated with CML-human serum albumin (HSA), its releasing effect was in the order VEGF>TNFalpha>PDGF-B. CML-HSA and CML-bovine serum albumin augmented the neovascularization in the cultured diabetic explant and their actions did not virtually differ. A monoclonal anti-CML antibody (6D12) inhibited the neovascularization in the advanced diabetes greater than that in the early diabetes. Inhibitory actions of anti-VEGF and anti-TNFalpha antibodies on the neovascularization were similar to that of the anti-CML antibody in the diabetes. In conclusion, CML adducts were accumulated and over-produced the actions of VEGF, TNFalpha and PDGF-B in the choroidal explant during diabetes in an age-dependent manner. TNFalpha and VEGF are likely to play a predominant role for the CML-induced choroidal neovascularization.
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PMID:Overproduction of N(epsilon)-(carboxymethyl)lysine-induced neovascularization in cultured choroidal explant of streptozotocin-diabetic rat. 1546 96

Protein kinase inhibitors can be effective in treating selected cancers, but most suppress several kinases. Imatinib mesylate has been useful in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and B cell acute lymphoblastic leukemia through the inhibition of BCR-ABL tyrosine kinase activity. Imatinib mesylate has also been shown to inhibit KIT, ARG, and platelet-derived growth factor receptors alpha and beta, and potentially other tyrosine kinases. We have produced a mutant allele of BCR-ABL (T315A) that is uniquely inhibitable by the small molecule 4-amino-1-tert-butyl-3-(1-naphthyl)pyrazolo[3,4-d]pyrimidine and used it to demonstrate that sole suppression of BCR-ABL activity was insufficient to eliminate BCR-ABL(+) KIT(+)-expressing immature murine myeloid leukemic cells. In contrast, imatinib mesylate effectively eliminated BCR-ABL(+) KIT(+)-expressing leukemic cells. In the cellular context of mature myeloid cells and Pro/Pre B cells that do not express KIT, monospecific BCR-ABL inhibition was quantitatively as effective as imatinib mesylate in suppressing cell growth and inducing apoptosis. These results suggest that the therapeutic effectiveness of small molecule drugs such as imatinib mesylate could be due to the inhibitor's ability to suppress protein kinases in addition to the dominant target.
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PMID:Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations. 1550 16

Imatinib is a tyrosine kinase inhibitor that suppresses the growth of bcr-abl-expressing chronic myeloid leukemia (CML) progenitor cells by blockade of the adenosine triphosphate (ATP)-binding site of the kinase domain of bcr-abl. Imatinib also inhibits the c-abl, platelet-derived growth factor (PDGF) receptor, abl-related gene (ARG) and stem-cell factor (SCF) receptor tyrosine kinases, and has been used clinically to inhibit the growth of malignant cells in patients with CML and gastrointestinal stromal tumors (GISTs). Although initially considered to have minimal effects of normal hematopoiesis, recent studies show that imatinib also inhibits the growth of some nonmalignant hematopoietic cells, including monocyte/macrophages. This inhibition could not be attributed to the known activity profile of imatinib. Here, we demonstrate for the first time that imatinib targets the macrophage colony-stimulating factor (M-CSF) receptor c-fms. Phosphorylation of c-fms was inhibited by therapeutic concentrations of imatinib, and this was not due to down-regulation in c-fms expression. Imatinib was also found to inhibit M-CSF-induced proliferation of a cytokine-dependent cell line, further supporting the hypothesis that imatinib affects the growth and development of monocyte and/or macrophages through inhibition of c-fms signaling. Importantly, these results identify an additional biologic target to those already defined for imatinib. Imatinib should now be assessed for activity in diseases where c-fms activation is implicated, including breast and ovarian cancer and inflammatory conditions.
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PMID:Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. 1563 41

We have previously reported that the Nepsilon (carboxymethyl)lysine (CML) adduct, a major structure of an advanced glycation end product, facilitates proliferation of CD34+ endothelial progenitor cells budded from cultured choroidal explants and produces immature vessel-like structures in fibrin gel. The CML adduct is accumulated and facilitates immature neovascularization in cultured choroidal explants of streptozotocin (STZ)-induced diabetic rat. The CML-enhanced neovascularization activity is associated with the actions of tumor necrosis factor (TNF) alpha, vascular endothelial growth factor and platelet-derived growth factor released from the choroidal explant (Kobayashi et al., Biol. Pharm. Bull., 27, 1382-1387 (2004); 27, 1565-1571 (2004)). The present study was investigated an inhibitory effect of a dihydropyridine calcium antagonist nifedipine on TNF alpha-induced choroidal neovascularization in the STZ-diabetic rat. TNF alpha (1-100 ng/ml) increased neovascularization of cultured choroidal explants in the age-matched normal rat but did not increase it in the diabetic rat. Anti-TNF alpha antibody (1 : 1000) decreased the neovascularization in the diabetic rat but not in the normal rat. Nifedipine (1 microM) inhibited TNF alpha-induced neovascularization of the normal choroidal explant in a non-competitive manner. Nifedipine (1 microM) also inhibited the diabetic state-induced neovascularization and its inhibitory action was reversed by TNF alpha (1-10 ng/ml). In conclusion, STZ-diabetic state facilitated choroidal neovascularization through the release of TNF alpha. Nifedipine inhibited the action of TNF alpha probably by blocking voltage-dependent Ca2+ channels in the endothelial progenitor cells of the diabetic choroid.
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PMID:Inhibitory effect of nifedipine on tumor necrosis factor alpha-induced neovascularization in cultured choroidal explants of streptozotocin-diabetic rat. 1568 77

Imatinib mesylate is a small molecule inhibitor of the c-Abl, platelet-derived growth factor (PDGF) receptor and c-Kit tyrosine kinases that is approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Glioblastoma multiforme is a highly malignant primary brain tumor that is usually treated with surgery and/or radiotherapy. Previous studies implicate an autocrine loop caused by high expression of PDGF and its receptor, PDGFR, in the proliferation of some glioblastomas. Here, we demonstrate that pretreatment of a human glioblastoma cell line, RuSi RS1, with imatinib significantly enhanced the cytotoxic effect of ionizing radiation. This effect was not seen in human breast cancer (BT20) and colon cancer (WiDr) cell lines. Whereas c-Abl and c-Kit were expressed about equally in the three cell lines, RuSi RS1 cells showed significantly higher expression of PDGFR-beta protein in comparison to BT20 and WiDr. Imatinib treatment of RuSi RS1 cells decreased overall levels of cellular tyrosine phosphorylation and specifically inhibited phosphorylation of PDGFR-beta, while c-Abl was not prominently activated in these cells. These results suggest that imatinib may have clinical utility as a radiosensitizer in the treatment of human glioblastoma, possibly through disruption of an autocrine PDGF/PDGFR loop.
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PMID:Imatinib mesylate radiosensitizes human glioblastoma cells through inhibition of platelet-derived growth factor receptor. 1572 3

Imatinib mesylate is a potent and specific tyrosine kinase inhibitor against c-ABL, BCR-ABL, and c-KIT, and has been demonstrated to be highly active in chronic myeloid leukemia and gastrointestinal stromal tumors. We examined the antifibrotic effects of imatinib using a bleomycin-induced lung fibrosis model in mice because imatinib also inhibits tyrosine kinase of platelet-derived growth factor receptors (PDGFRs). Imatinib inhibited the growth of primary murine lung fibroblasts and the autophosphorylation of PDGFR-beta induced by PDGF. Administration of imatinib significantly prevented bleomycin-induced pulmonary fibrosis in mice, partly by reducing the number of mesenchymal cells incorporating bromodeoxyuridine. Analysis of bronchoalveolar lavage cells demonstrated that imatinib did not suppress early inflammation on Days 7 and 14 caused by bleomycin. These results suggest that imatinib has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that imatinib might be useful for the treatment of pulmonary fibrosis in humans.
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PMID:Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. 1573 62

The hallmark characteristics of cancer include an unrestrained proliferation involving activation of growth signals, loss of negative regulation and dysfunctional apoptotic pathways. Targeting abnormal cell signalling pathways should provide a more selective approach to cancer treatment than conventional cytotoxic chemotherapy. Tyrosine kinases play an essential role in the signalling pathways involved in the control of cellular proliferation and growth. Imatinib is a small-molecule tyrosine kinase inhibitor of the ABL fusion gene, platelet derived growth factor receptors (PDGFR) and KIT. This agent has demonstrated considerable activity in chronic myeloid leukaemia (CML) by inhibiting the BCR-ABL fusion protein and gastrointestinal stromal tumours (GISTs), which are predominantly driven by activating mutations in KIT. A number of other rare conditions are also responsive, for example, dermatofibrosarcoma protuberans, which is driven by a chromosomal translocation involving PDGF-B and Col1A1, resulting in overexpression of PDGF-B, and hypereosinophillic syndrome, which can be caused by activating PDGFR mutations. The pivotal registration study for newly diagnosed CML was a large randomised trial comparing 400 mg/day of imatinib to a combination of IFN-alpha and cytarabine, which demonstrated a significantly higher complete haematological and cytogenetic response rate in the imatinib arm. In the case of GIST a randomised study in patients with inoperable or metastatic disease explored doses of 400 - 600mg and reported a response rate of > 50% in each arm plus disease stabilisation and an improvement in performance status. Large randomised trials have subsequently been performed, comparing 400 with 800mg/day. The first to report indicates that the larger dose is associated with improved progression-free survival, although it is not yet known whether or not this will translate into a difference in overall survival. The most common KIT mutation involves exon 11 and is associated with a statistically significant better response and prognosis compared with other mutations or no detectable mutations. Mutational analysis is likely to become increasingly important in the selection of patients for neoadjuvant and adjuvant treatment and in helping to understand the nature of acquired resistance.
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PMID:The development and application of imatinib. 1579 12

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.
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PMID:The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. 1589 16

Imatinib is a potent and selective inhibitor of the protein tyrosine kinase Bcr-Abl, platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta) and KIT. Imatinib is approved for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST), which have dysregulated activity of an imatinib-sensitive kinase as the underlying pathogenetic feature. Pharmacokinetic studies of imatinib in healthy volunteers and patients with CML, GIST and other cancers show that orally administered imatinib is well absorbed, and has an absolute bioavailability of 98% irrespective of oral dosage form (solution, capsule, tablet) or dosage strength (100 mg, 400 mg). Food has no relevant impact on the rate or extent of bioavailability. The terminal elimination half-life is approximately 18 hours. Imatinib plasma concentrations predictably increase by 2- to 3-fold when reaching steady state with 400mg once-daily administration, to 2.6 +/- 0.8 microg/mL at peak and 1.2 +/- 0.8 microg/mL at trough, exceeding the 0.5 microg/mL (1 micromol/L) concentrations needed for tyrosine kinase inhibition in vitro and leading to normalisation of haematological parameters in the large majority of patients with CML irrespective of baseline white blood cell count. Imatinib is approximately 95% bound to human plasma proteins, mainly albumin and alpha1-acid glycoprotein. The drug is eliminated predominantly via the bile in the form of metabolites, one of which (CGP 74588) shows comparable pharmacological activity to the parent drug. The faecal to urinary excretion ratio is approximately 5:1. Imatinib is metabolised mainly by the cytochrome P450 (CYP) 3A4 or CYP3A5 and can competitively inhibit the metabolism of drugs that are CYP3A4 or CYP3A5 substrates. Interactions may occur between imatinib and inhibitors or inducers of these enzymes, leading to changes in the plasma concentration of imatinib as well as coadministered drugs. Hepatic and renal dysfunction, and the presence of liver metastases, may result in more variable and increased exposure to the drug, although typically not necessitating dosage adjustment. Age (range 18-70 years), race, sex and bodyweight do not appreciably impact the pharmacokinetics of imatinib.
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PMID:Clinical pharmacokinetics of imatinib. 1612 78

The annual meeting of the American Association for Cancer Research (AACR) provided a panoramic view of new developments and trends in cancer research. In the area of new drug development, a recurrent theme was receptor tyrosine kinase (TK) inhibitors, with multi-targeted, small molecule inhibitors - highly potent against a family of receptors such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor (PDGFR) and the receptor tyrosine kinase KIT - taking centre stage. Several agents interfering with intracellular targets that are components of key oncogenic signaling pathways, such as RAF kinase, phosphatidylinositol 3-kinase (PI3K)/Akt or Src, are in preclinical and early clinical development. "Addictive" targets, such as the Bcr-Abl fusion protein in chronic myeloid leukemia (CML), are critical for maintaining the malignant phenotype and hence represent an Achilles' heel for selective drugs. Significantly, novel targeted therapeutics currently in clinical development do not generally lead to cures or long-term survival for most intractable cancers; resistance may eventually develop. Anti-metastatic agents and anti-adhesion drugs, which collectively act on tumor cell-stroma interactions (anti-stromal therapy), are also actively pursued. In addition, forms of cell death other than apoptosis - cellular senescence, cancer cell-specific cell-cycle processes and the hypoxic environment - are being explored in order to identify novel targets for more selective therapy. This report also highlights developments aimed at more safe and effective drug combinations. Evaluating drug combinations, and elucidating the rationale for combinations of old (cytotoxic) and new (biological) anticancer agents, are promising research areas and taxane-based combinations are presented as examples. The report is based on presentations at AACR 2005 and related publications of the first half of 2005.
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PMID:Anticancer therapeutics: "Addictive" targets, multi-targeted drugs, new drug combinations. 1615


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