43 results on '"Protein Tyrosine Kinase Inhibitor"'
Search Results
2. Inflammatory Potency of Activin A : Effect on Prostanoid and Nitric Oxide Formation
- Author
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Nüsing, Rolf M., Barsig, Johannes, Honn, Kenneth V., editor, Marnett, Lawrence J., editor, Nigam, Santosh, editor, Jones, Robert L., editor, and Wong, Patrick Y.-K., editor
- Published
- 1997
- Full Text
- View/download PDF
3. Response to Webb et al. Top Ten Tips Palliative Care Clinicians Should Know about Caring for Patients with Hematologic Malignancies (DOI: 10.1089/jpm.2019.0332).
- Published
- 2020
4. Response to Webb et al. Top Ten Tips Palliative Care Clinicians Should Know about Caring for Patients with Hematologic Malignancies (DOI: 10.1089/jpm.2019.0332).
- Published
- 2020
5. Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer.
- Abstract
Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 + T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.Copyright © 2019 American Association for Cancer Research.
- Published
- 2020
6. Response to Webb et al. Top Ten Tips Palliative Care Clinicians Should Know about Caring for Patients with Hematologic Malignancies (DOI: 10.1089/jpm.2019.0332).
- Published
- 2020
7. Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer.
- Abstract
Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 + T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.Copyright © 2019 American Association for Cancer Research.
- Published
- 2020
8. Hunig's base catalyzed synthesis of new 1-(2,3-dihydro-1H-inden-1-yl)-3-aryl urea/thiourea derivatives as potent antioxidants and 2HCK enzyme growth inhibitors
- Abstract
A series of 1-(2,3-dihydro-1H-indan-1-yl)-3-aryl urea/thiourea derivatives (4a-j) have been synthesized from the reaction of 2,3-dihydro-1H-inden-1-amine (2) with various aryl isocyanates/isothiocyanates (3a-j) by using N,N-DIPEA base (Hunig's base) catalyst in THF at reflux conditions. All of them are structurally confirmed by spectral (IR, 1H & 13C NMR and MASS) and elemental analysis and screened for their in-vitro antioxidant activity against DPPH and NO free radicals and found that compounds 4b, 4i, 4h & 4g are potential antioxidants. The obtained in vitro results were compared with the molecular docking, ADMET, QSAR and bioactivity study results performed for them and identified that the recorded in silico binding affinities were observed in good correlation with the in vitro antioxidant results. The Molecular docking analysis had unveiled the strong hydrogen bonding interactions of synthesized ligands with ARG 160 residue of protein tyrosine kinase (2HCK) enzyme and plays an effective role in its inhibition. Toxicology studies have assessed the potential risks of 4a-j and inferred that all of them were in the limits of potential drugs. The conformational analysis of 4a-j inferred that the urea/thiourea spacer linking 2,3-dihydro-1H-inden-1-amino and substituted aryl units has facilitated all these molecules to effectively bind with ARG 160 amino acid residue present on the α-helix of the protein tyrosine kinase (2HCK) enzyme specifically on chain A of hemopoetic cell kinase. Collectively this study has established a relationship between the antioxidant potentiality and ligands binding with ARG 160 amino acid residue of chain A of 2HCK enzyme to inhibit its growth as well as proliferation of reactive oxygen species in vivo. © 2019 Elsevier Inc.
- Published
- 2020
9. Hunig's base catalyzed synthesis of new 1-(2,3-dihydro-1H-inden-1-yl)-3-aryl urea/thiourea derivatives as potent antioxidants and 2HCK enzyme growth inhibitors
- Author
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Swetha Vallela, Visweswara Rao Pasupuleti, Grigoriy V. Zyryanov, Venkataramana Lachhi Reddy, Naga Raju Chamarthi, Jaya Shree Anireddy, and Vijay Kumar Reddy Avula
- Subjects
PHYSICAL CHEMISTRY ,Antioxidant ,medicine.medical_treatment ,IC50 ,01 natural sciences ,Biochemistry ,Antioxidants ,PROTEIN TYROSINE KINASE ,CELL NUCLEUS RECEPTOR ,CHEMISTRY ,ANTIOXIDANT ,DRUG ABSORPTION ,ELEMENTAL ANALYSIS ,Drug Discovery ,HUMAN CELL ,Urea ,chemistry.chemical_classification ,HUMAN ,THIOUREA DERIVATIVE ,DRUG DISTRIBUTION ,QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ,LIGANDS ,PROTEIN KINASE INHIBITORS ,IN VITRO STUDY ,PROTEIN-TYROSINE KINASES ,Stereochemistry ,Radical ,UREA/THIO-UREA DERIVATIVE ,CARBON NUCLEAR MAGNETIC RESONANCE ,Residue (chemistry) ,QUANTITATIVE STRUCTURE ACTIVITY RELATION ,MDCK CELL LINE ,2,3-DIHYDRO-1H-INDEN-1-AMINE ,NONHUMAN ,Humans ,FREE RADICAL ,CACO-2 CELL LINE ,DRUG METABOLISM ,Molecular Biology ,010405 organic chemistry ,CATALYSIS ,0104 chemical sciences ,1,1 DIPHENYL 2 PICRYLHYDRAZYL ,PROTON NUCLEAR MAGNETIC RESONANCE ,chemistry ,CACO-2 CELLS ,THIOUREA ,MOLECULAR DOCKING STUDIES ,NEUROPROTECTIVE AGENT ,BLOOD-BRAIN BARRIER ,DRUG EXCRETION ,ELECTROSPRAY MASS SPECTROMETRY ,MOLECULAR DOCKING SIMULATION ,Quantitative Structure-Activity Relationship ,UNCLASSIFIED DRUG ,Ligands ,chemistry.chemical_compound ,PROTEIN KINASE INHIBITOR ,ANTIOXIDANTS ,MOLECULAR DOCKING ,1 (2,3 DIHYDRO 1H INDEN 1 YL) 3 (4 FLUOROPHENYL)UREA ,PRIORITY JOURNAL ,2HCK ENZYME GROWTH INHIBITION ,CATALYST ,Hydrogen bond ,Thiourea ,HUMANS ,Protein-Tyrosine Kinases ,Molecular Docking Simulation ,NEUROPROTECTIVE AGENTS ,Neuroprotective Agents ,BLOOD BRAIN BARRIER ,Blood-Brain Barrier ,ASCORBIC ACID ,NUCLEOPHILICITY ,PHOSPHOTRANSFERASE INHIBITOR ,ADMET PROPERTIES ,PLASMA PROTEIN BINDING ,Catalysis ,medicine ,ARTICLE ,Protein Kinase Inhibitors ,Aryl ,DRUG SYNTHESIS ,Organic Chemistry ,PROTEIN TYROSINE KINASE INHIBITOR ,UREA DERIVATIVE ,ULTRAVIOLET RADIATION ,CONTROLLED STUDY ,010404 medicinal & biomolecular chemistry ,Enzyme ,ANIMAL CELL ,CELL PROLIFERATION ,THIN LAYER CHROMATOGRAPHY ,LIGAND ,UREA ,Caco-2 Cells ,PROTEINASE INHIBITOR ,ANTIOXIDANT ACTIVITY - Abstract
A series of 1-(2,3-dihydro-1H-indan-1-yl)-3-aryl urea/thiourea derivatives (4a-j) have been synthesized from the reaction of 2,3-dihydro-1H-inden-1-amine (2) with various aryl isocyanates/isothiocyanates (3a-j) by using N,N-DIPEA base (Hunig's base) catalyst in THF at reflux conditions. All of them are structurally confirmed by spectral (IR, 1H & 13C NMR and MASS) and elemental analysis and screened for their in-vitro antioxidant activity against DPPH and NO free radicals and found that compounds 4b, 4i, 4h & 4g are potential antioxidants. The obtained in vitro results were compared with the molecular docking, ADMET, QSAR and bioactivity study results performed for them and identified that the recorded in silico binding affinities were observed in good correlation with the in vitro antioxidant results. The Molecular docking analysis had unveiled the strong hydrogen bonding interactions of synthesized ligands with ARG 160 residue of protein tyrosine kinase (2HCK) enzyme and plays an effective role in its inhibition. Toxicology studies have assessed the potential risks of 4a-j and inferred that all of them were in the limits of potential drugs. The conformational analysis of 4a-j inferred that the urea/thiourea spacer linking 2,3-dihydro-1H-inden-1-amino and substituted aryl units has facilitated all these molecules to effectively bind with ARG 160 amino acid residue present on the α-helix of the protein tyrosine kinase (2HCK) enzyme specifically on chain A of hemopoetic cell kinase. Collectively this study has established a relationship between the antioxidant potentiality and ligands binding with ARG 160 amino acid residue of chain A of 2HCK enzyme to inhibit its growth as well as proliferation of reactive oxygen species in vivo. © 2019 Elsevier Inc. One of the authors Dr. Avula Vijay Kumar Reddy is thankful to Ural Federal University, Yekaterinburg, Russian Federation for providing Postdoctoral Fellowship.
- Published
- 2019
10. Synthesis, characterization, electrochemical behavior and in vitro protein tyrosine kinase inhibitory activity of the cymene-halogenobenzohydroxamato [Ru(η6-cymene)(bha)Cl] complexes
- Author
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Shang, Xianmei, Silva, Telma F.S., Martins, Luísa M.D.R.S., Li, Qingshan, Guedes da Silva, M. Fátima C., Kuznetsov, Maxim L., and Pombeiro, Armando J.L.
- Subjects
- *
COMPLEX compounds synthesis , *PROTEIN-tyrosine kinases , *ENZYME inhibitors , *ORGANORUTHENIUM compounds , *ELECTROCHEMICAL analysis , *CYMENE , *SUBSTITUTION reactions - Abstract
Abstract: The ruthenium(II)–cymene complexes [Ru(η6-cymene)(bha)Cl] with substituted halogenobenzohydroxamato (bha) ligands (substituents = 4-F, 4-Cl, 4-Br, 2,4-F2, 3,4-F2, 2,5-F2, 2,6-F2) have been synthesized and characterized by elemental analysis, IR, 1H NMR, 13C NMR, cyclic voltammetry and controlled-potential electrolysis, and density functional theory (DFT) studies. The compositions of their frontier molecular orbitals (MOs) were established by DFT calculations, and the oxidation and reduction potentials are shown to follow the orders of the estimated vertical ionization potential and electron affinity, respectively. The electrochemical E L Lever parameter is estimated for the first time for the various bha ligands, which can thus be ordered according to their electron-donor character. All complexes exhibit very strong protein tyrosine kinase (PTK) inhibitory activity, even much higher than that of genistein, the clinically used PTK inhibitory drug. The complex containing the 2,4-difluorobenzohydroxamato ligand is the most active one, and the dependences of the PTK activity of the complexes and of their redox potentials on the ring substituents are discussed. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
11. Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again?
- Author
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HLUSHCHUK, RUSLAN, MAKANYA, ANDREW N., and DJONOV, VALENTIN
- Abstract
Inhibitors of angiogenesis and radiation induce compensatory changes in the tumor vasculature both during and after cessation of treatment. In numerous preclinical studies, angiogenesis inhibitors were shown to be efficient in the treatment of many pathological conditions, including solid cancers. In most clinical trials, however, this approach turned out to have no significant effect, especially if applied as monotherapy. Recovery of tumors after therapy is a major problem in the management of cancer patients. The mechanisms underlying tumor recovery (or therapy resistance) have not yet been explicitly elucidated. This review deals with the transient switch from sprouting to intussusceptive angiogenesis, which may be an adaptive response of tumor vasculature to cancer therapy that allows the vasculature to maintain its functional properties. Potential candidates for molecular targeting of this angioadaptive mechanism are yet to be elucidated in order to improve the currently poor efficacy of contemporary antiangiogenic therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
12. Herbal formulation, Yukmi-jihang-tang-Jahage, regulates bone resorption by inhibition of phosphorylation mediated by tyrosine kinase Src and cyclooxygenase expression
- Author
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Jin, Un-Ho, Kim, Dong-Il, Lee, Tae-Kyun, Lee, Dong-Nyung, Kim, June-Ki, Lee, In-Seon, and Kim, Cheorl-Ho
- Subjects
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HERBAL medicine , *CYCLOOXYGENASE 2 , *PROTEIN-tyrosine kinases , *INTERLEUKINS , *CYTOKINES - Abstract
Abstract: Anti-bone resorption properties of the Korean herbal medicine, Yukmi-jihang-tang (YJ), which is comprised of seven herbs such as Rehmannia glutinosa Libosch, Dioscorea japonica THUNB, Cornus officinalis SIEB et. ZUCC, Smilax glabra ROXB, Paeonia suffruticosa ANDR, Alisma platago-aquatica var. orientale SAMUELS and Hominis placenta, were investigated. Cyclooxygenase-2 (COX-2) and tyrosine kinase involve on prostaglandin E2 (PGE2) production in mouse calvarial osteoblasts stimulated by cytokine interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and/or interleukin-6 (IL-6). IL-1β and IL-6 and to a lesser extent TNF-α, enhanced COX-2 mRNA levels in calvarial osteoblasts. TGF-β, YJ (100μg/ml) and their combinations of YJ+TGF-β reduced the COX-2 mRNA level, PGE2 biosynthesis and bone resorption induced by IL-1β, TNF-α, IL-6 or their combination. Finally, YJ inhibits in vitro and in vivo bone resorption by inhibition of phosphorylation of peptide substrates. The parathyroid hormone-induced bone resorption in mouse fetal long bone cultures was inhibited with an IC50 of 16μg/ml. YJ dose-dependently reduced the hypercalcemia induced in mice by IL-1β and partly prevented bone loss and microarchitectural changes in young ovariectomized rats, showing that the protective effect on bone was exerted via the inhibition of bone resorption. These results indicate that the synergy between IL-β, TNF-α, IL-6 on PGE2 production is due to an enhanced gene expression of COX-2 and that tyrosine kinase(s) are involved in the signal transduction of COX-2 in mouse calvarial osteoblasts. Thus, YJ as a possible Src family kinase inhibitor may be useful for the treatment of diseases associated with elevated bone loss. This result also suggested that the YJ extracts is effective for bone resorptive action in bone cells. [Copyright &y& Elsevier]
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- 2006
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13. Effects of TGF-β, TNF-α, IL-β and IL-6 alone or in combination, and tyrosine kinase inhibitor on cyclooxygenase expression, prostaglandin E2 production and bone resorption in mouse calvarial bone cells
- Author
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Park, Young-Guk, Kang, Sung-Koo, Kim, Won-Jin, Lee, Youn-Choon, and Kim, Cheorl-Ho
- Subjects
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AMINO acids , *TYROSINE , *PROTEIN-tyrosine kinases , *MESSENGER RNA - Abstract
Cyclooxygenase-2 (COX-2) and tyrosine kinase, which are involved in the biosynthesis of prostaglandin E2 (PGE2) in mouse calvarial osteoblasts, are stimulated by cytokine interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and/or interleukin-6 (IL-6). IL-1β and IL-6 and, to a lesser extent, TNF-α, enhances COX-2 mRNA levels in calvarial osteoblasts. Simultaneous treatment with IL-6 and IL-1β and TNF-α resulted in enhanced COX-2 mRNA levels accompanied by the cooperative stimulation of PGE2 biosynthesis compared to cells treated with IL-1β or TNF-α or IL-6 alone. In contrast, the presence of TGF-β reduced COX-2 mRNA level, PGE2 biosynthesis and bone resorption induced by IL-1β, TNF-α, IL-6 or a combination thereof. However, neither IL-1β, TNF-α, IL-6 nor a combination of IL-1β, TNF-α, IL-6 enhanced COX-1 mRNA levels in calvarial osteoblasts. A novel Src tyrosine kinase inhibitor, Herbimycin A (HERB), reduced COX-2 mRNA levels as well as PGE2 production induced by IL-1β, TNF-α and IL-6 or a combination of IL-1β, TNF-α, IL-6, whereas COX-1 mRNA levels remained unaffected. Finally, HERB was found to inhibit in vitro bone resorption. These results indicate that the cooperative effects of IL-β, TNF-α, IL-6 on PGE2 production are due to the enhanced expression of the COX-2 gene and that tyrosine kinase(s) are involved in COX-2 signal transduction in mouse calvarial osteoblasts. Thus, the Src family of kinase inhibitors may be useful in treating diseases associated with elevated bone loss. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
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14. Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione
- Author
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Hori, Hitoshi, Nagasawa, Hideko, Uto, Yoshihiro, Ohkura, Kazuto, Kirk, Kenneth L., Uehara, Yoshimasa, and Shimamura, Mariko
- Subjects
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PROTEIN-tyrosine kinases , *HYPOXEMIA , *METHYLATION , *ANTINEOPLASTIC agents , *ALKYLATION , *HEPATOTOXICOLOGY - Abstract
We review in this report our strategy and tactics for the design of 2-hydroxyarylidene-4-cyclopentene-1,3-diones as protein tyrosine kinase (PTK) inhibitors having low mitochondrial toxicities and/or hypoxia-targeting function. We based our synthetic design on an innovative pharmacophore, 2-methylene-4-cyclopentene-1,3-dione. We first showed the effectiveness of this pharmacophore in the development of 2-methylene-4-cyclopentene-1,3-dione as PTK inhibitor that have lower mitochondrial toxicity than the potent PTK inhibitor tyrphostin AG17. Our results show that the cyclopentenedione-derived TX-1123 is a more potent antitumor tyrphostin and also shows lower mitochondrial toxicity than the malononitrile-derived AG17. The O-methylation product of TX-1123 (TX-1925) retained its tyrphostin-like properties, including mitochondrial toxicity and antitumor activities. However, the methylation product of AG17 (TX-1927) retained its tyrphostin-like antitumor activities, but lost its mitochondrial toxicity. Our comprehensive evaluation of these agents with respect to PTK inhibition, mitochondrial inhibition, antitumor activity, and hepatotoxicity demonstrates that PTK inhibitors TX-1123 and TX-1925 are more promising candidates for antitumor agents than tyrphostin AG17. Secondly, as a further investigation of the promising power of this 4-cyclopentene-1,3-dione as an innovative pharmacophore, we discuss our strategy of development of hypoxia-targeting PTK inhibitor TX-1123 analogues, 2-nitroimidazole-aminomethylenecyclopentenediones, such as TX-2036, for cancer treatment, especially for pancreatic cancers, which have a high level of hypoxia. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
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15. Favourable outcome of de novo advanced phases of childhood chronic myeloid leukaemia
- Author
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Meinolf Suttorp, Natacha Maledon, Frédéric Millot, Joelle Guilhot, Adalet Meral Güneş, Krzysztof Kałwak, Bursa Uludağ Üniversitesi/Tıp Fakültesi/Dahili Tıp Bilimleri/Çocuk Sağlığı Ve Hastalıkları Bölümü., Güneş, Adalet Meral, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pediatric Hematology and Oncology (MHH), and Hannover Medical School [Hannover] (MHH)
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Time Factors ,Survival ,Databases, Factual ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Childhood leukemia ,Recommendations ,Leukemia relapse ,Treatment response ,Cancer staging ,Time factor ,European LeukemiaNet ,0302 clinical medicine ,Immunophenotyping ,Cancer Survivors ,hemic and lymphatic diseases ,Pathology ,Overall survival ,Molecular Targeted Therapy ,Registries ,Age of Onset ,Child ,Children ,Priority journal ,Chronic myeloid leukemia ,Stem cell transplantation ,Hematopoietic Stem Cell Transplantation ,Register ,Multicenter study ,3. Good health ,Chronic Myeloid Leukemia ,Imatinib ,Protein Tyrosine Kinase Inhibitor ,Clinical trial ,Haematopoiesis ,Retrospective study ,Treatment Outcome ,Oncology ,Molecularly targeted therapy ,030220 oncology & carcinogenesis ,Child, Preschool ,International registry ,Interphase-fish ,Cml patients ,Protein kinase inhibitor ,Cancer survivor ,Disease Progression ,Female ,Cancer chemotherapy ,Chronic myelogenous leukemia ,medicine.drug ,Human ,Adult ,Adverse event ,medicine.medical_specialty ,Adolescent ,Lymphoid blast crisis ,Major clinical study ,Blastic Phase ,Article ,03 medical and health sciences ,Internal medicine ,Advanced cancer ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Factual database ,Prospective study ,Disease exacerbation ,Mortality ,neoplasms ,Survival rate ,Protein tyrosine kinase inhibitor ,Protein Kinase Inhibitors ,Chronic myeloid leukaemia ,Neoplasm Staging ,Tyrosine kinase inhibitors ,Chemotherapy ,business.industry ,Prognostic-factors ,Infant ,Follow up ,Transplantation ,030104 developmental biology ,Onset age ,Preschool child ,Comparative study ,business ,Controlled study - Abstract
Background Chronic myeloid leukaemia (CML) is very rare in children. The aim of the study is to report the experience within the I-CML-Ped study in children and adolescents presenting at diagnosis with advanced phase disease and to describe their characteristics and outcomes. Methods Of 479 children and adolescents enrolled in the international registry for childhood chronic myeloid leukaemia (I-CML-Ped Study; www.clinicaltrials.gov NCT01281735 ), 36 children (7.5%) presented at initial diagnosis with CML in advanced phase according to the European LeukemiaNet criteria. Results Nineteen (4%) patients were diagnosed in accelerated phase (CML-AP), and among the 17 patients (3.5%) diagnosed in blastic phase (CML-BP), 70% presented with lymphoid immunophenotype. Initial treatment of CML-AP/CML-BP consisted of tyrosine kinase inhibitors (TKIs) with or without chemotherapy, leading to complete haematologic response in 33 of 36 (92%) patients. Seventeen patients proceeded to haematopoietic stem cell transplantation. At the last follow-up, 18 of 19 patients with de novo CML-AP are alive in at least major molecular response (MMR) (n = 16), in progression (n = 1) or in molecular relapse (n = 1) and 13 of 17 patients with de novo CML-BP are alive in at least MMR. Five-year overall survival rates are 94% (95% confidence interval [CI]: 66%–99%) and 74% (95% CI: 44%–89%) for patients diagnosed in CML-AP and CML-BP, respectively. Conclusion Children with advanced phase at diagnosis of CML seem to have a better survival rate than that reported for advanced phases evolving under TKI treatment.
- Published
- 2018
16. Ynamide Click chemistry in development of triazole VEGFR2 TK modulators
- Author
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Gilles Hanquet, Gabriela Addová, Juraj Dobiaš, Margaréta Vojtičková, Andrej Boháč, Rengul Cetin-Atalay, and Deniz Yildirim
- Subjects
Oxazole/1,2,3-triazole isosteric replacement ,Molecular model ,protein tyrosine kinase inhibitor ,Protein Data Bank (RCSB PDB) ,4 [4 [5 (ethylsulfonyl) 2 methoxyphenylamino] 1h 1,2,3 triazol 1 yl] 2 (pyridin 2 yl)phenol ,VEGFR2 tyrosine kinase inhibition ,CuACC Click chemistry ,chemistry.chemical_compound ,Drug Discovery ,vasculotropin receptor 2 ,phosphatidylinositol 3 kinase ,Oxazole ,carcinoma cell line ,Molecular Structure ,Chemistry ,1,2,3 triazole derivative ,General Medicine ,unclassified drug ,enzyme activity ,PI3K/Akt pathway ,Alkynes ,click chemistry ,Click chemistry ,Cytotoxic activity in Huh-7 and Mahlavu ,cytotoxicity ,chemical reaction ,liver cell carcinoma ,Stereochemistry ,Triazole ,Antineoplastic Agents ,Article ,Structure-Activity Relationship ,Cell Line, Tumor ,Humans ,Structure–activity relationship ,controlled study ,human ,Ynamide ,Binding site ,Protein Kinase Inhibitors ,Cell Proliferation ,Pharmacology ,Dose-Response Relationship, Drug ,binding site ,human cell ,oxazole ,Organic Chemistry ,molecular docking ,Triazoles ,Amides ,Vascular Endothelial Growth Factor Receptor-2 ,drug structure ,concentration response ,Docking (molecular) ,protein kinase B ,drug synthesis ,Click Chemistry ,molecular model ,Drug Screening Assays, Antitumor ,hepatocellular carcinoma cell lines - Abstract
Structure novelty, chemical stability and synthetic feasibility attracted us to design 1,2,3-triazole compounds as potential inhibitors of VEGFR2 tyrosine kinase. Novel triazoles T1-T7 were proposed by oxazole (AAZ from PDB: 1Y6A)/1,2,3-triazole isosteric replacement, molecular modelling and docking. In order to enable synthesis of T1-T7 we developed a methodology for preparation of ynamide 22. Compound 22 was used for all Click chemistry reactions leading to triazoles T1-T3 and T6-T7. Among the obtained products, T1, T3 and T7 specifically bind VEGFR2 TK and modulate its activity by concentration dependent manner. Moreover predicted binding poses of T1-T7 in VEGFR2 TK were similar to the one known for the oxazole inhibitor AAZ (PDB: 1Y6A). Unfortunately the VEGFR2 inhibition by triazoles e.g. T3 and T7 is lower than that determined for their oxazole bioisosters T3-ox and AAZ, resp. Different electronic properties of 1,2,3-triazole/oxazole heterocyclic rings were proposed to be the main reason for the diminished affinity of T1-T3, T6 and T7 to an oxazole AAZ inhibitor binding site in VEGFR2 TK (PDB: 1Y6A or 1Y6B). Moreover T1-T3 and T6 were screened on cytotoxic activity against two human hepatocellular carcinoma cell lines. Selective cytotoxic activity of T2 against aggressive Mahlavu cells has been discovered indicating possible affinity of T2 to Mahlavu constitutionally active PI3K/Akt pathway. © 2015 Elsevier Masson SAS.
- Published
- 2015
17. Sources and biological activities of marine sulfated steroids
- Author
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Carvalhal F., Correia-da-Silva M., Sousa E., Pinto M., Kijjoa A., and CIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental
- Subjects
antivirus agent ,guanosine diphosphate ,antiproliferative activity ,marine environment ,protein tyrosine kinase inhibitor ,microtubule assembly ,biological activity ,antineoplastic activity ,Review ,protein kinase C inhibitor ,antiparasitic agent ,pregnane X receptor ,angiogenesis ,antibacterial activity ,antibiotic agent ,antifungal agent ,human ,antineoplastic agent ,structure activity relation ,nonhuman ,steroid ,antifungal activity ,apoptosis ,protein tyrosine kinase ,antiinflammatory activity ,clinical trial ,antithrombocytic agent ,protein kinase C delta ,antifouling agent ,beta secretase 1 ,priority journal ,antihypertensive activity ,cardiovascular agent ,antiviral activity ,osteoblast ,matrix metalloproteinase 14 ,hemolysis ,antiinflammatory agent ,farnesoid X receptor - Abstract
Marine environment is rich in structurally unique molecules and can be an inspiring source of novel drugs. Currently, six marine-derived drugs are in the market with FDA approval and several more are in the clinical pipeline. Structurally diverse and complex secondary metabolites have been isolated from the marine world and these include sulfated steroids. Biological activities of nearly 150 marine sulfated steroids reported from 1978 to 2017 are compiled and described, namely antimicrobial, antitumor, cardiovascular and antifouling activities. Structure–activity relationship for each activity is discussed. © 2018 Society for Endocrinology. This work was supported through national funds provided by FCT/MCTES – Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE – Programa Operacional Factores de Competitividade (POFC) programme, under the projects PTDC/ MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599 PPCDT – Promover a Produção Científica e Desenvolvimento Tecnológico e a Constituição de Redes Temáticas) and PTDC/AAG-TEC/0739/2014 (reference POCI-01-0145-FEDER-016793; Project 9471 RIDTI – Reforçar a Investigação, o Desenvolvimento Tecnológico e a Inovação) in the framework of the programme PT2020. The author acknowledges the Strategic Funding UID/Multi/04423/2013 provided by FCT – Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the programme PT2020.
- Published
- 2018
18. Clinical outcomes in patients with renal cell carcinoma with venous tumour thrombus: 10-year single centre experience.
- Abstract
Introduction and Objectives: To evaluate long-term outcomes in patients undergoing radical nephrectomy and tumour thrombectomy at Monash Health over the last 10 years. Method(s): We performed a retrospective analysis of 27 patients undergoing surgery between 2005 and 2015. Follow-up data were available for 24 patients. Data on clinical presentation, laboratory and imaging investigations, tumour characteristics, staging, operative details, complications, and long-term follow-up were evaluated. Result(s): Twenty-seven patients were included in the study (19 males, 8 females). Patients aged between 37- 80 years with a mean age of 61 years. Eighteen patients (67%) had nodal or distant metastasis at the time of diagnosis. According to AJCC tumour thrombus classifications - level I in 13 patients (48%), level II in 5 patients (19%) and level III in 2 patients (7%). Post-operative complications of Clavien-Dindo grade III or above occurred in 4 patients (15%). Four patients (15%) received adjuvant chemotherapy and 10 patients (37%) received tyrosine-kinase inhibitor (TKI) therapy post-operatively. Mean follow-up period in this cohort was 62 months. At the time of follow-up 21 patients (78%) were still alive. Of the 6 deaths, 4 patients died of metastatic RCC, 1 patient died during re-operation and the cause of death was not recorded for the last patient. Conclusion(s): Radical nephrectomy and tumour thrombectomy offer reasonable long-term survival in patients with locally advanced RCC. The complication rates at our centre are comparable with that of the literature.
- Published
- 2017
19. Clinical outcomes in patients with renal cell carcinoma with venous tumour thrombus: 10-year single centre experience.
- Abstract
Introduction and Objectives: To evaluate long-term outcomes in patients undergoing radical nephrectomy and tumour thrombectomy at Monash Health over the last 10 years. Method(s): We performed a retrospective analysis of 27 patients undergoing surgery between 2005 and 2015. Follow-up data were available for 24 patients. Data on clinical presentation, laboratory and imaging investigations, tumour characteristics, staging, operative details, complications, and long-term follow-up were evaluated. Result(s): Twenty-seven patients were included in the study (19 males, 8 females). Patients aged between 37- 80 years with a mean age of 61 years. Eighteen patients (67%) had nodal or distant metastasis at the time of diagnosis. According to AJCC tumour thrombus classifications - level I in 13 patients (48%), level II in 5 patients (19%) and level III in 2 patients (7%). Post-operative complications of Clavien-Dindo grade III or above occurred in 4 patients (15%). Four patients (15%) received adjuvant chemotherapy and 10 patients (37%) received tyrosine-kinase inhibitor (TKI) therapy post-operatively. Mean follow-up period in this cohort was 62 months. At the time of follow-up 21 patients (78%) were still alive. Of the 6 deaths, 4 patients died of metastatic RCC, 1 patient died during re-operation and the cause of death was not recorded for the last patient. Conclusion(s): Radical nephrectomy and tumour thrombectomy offer reasonable long-term survival in patients with locally advanced RCC. The complication rates at our centre are comparable with that of the literature.
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- 2017
20. Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents
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Chi Kong Li, André Baruchel, Michael Dworzak, Joelle Guilhot, Farah Roula, Krzysztof Kałwak, Petr Sedlacek, Eveline S. J. M. de Bont, Birgitte Lausen, Emilia Kaiserova, Barbara De Moerloose, Srdjana Culic, Frédéric Millot, Andrea Biondi, Adalet Meral Güneş, Meinolf Suttorp, Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Hematoloji Anabilim Dalı., Güneş, Adalet Meral, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Stem Cell Aging Leukemia and Lymphoma (SALL), Millot, F, Guilhot, J, Suttorp, M, Gunes, A, Sedlacek, P, De Bont, E, Li, C, Kalwak, K, Lausen, B, Culic, S, Dworzak, M, Kaiserova, E, De Moerloose, B, Roula, F, Biondi, A, and Baruchel, A
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Registrie ,Male ,Scoring system ,Intermediate risk patient ,0302 clinical medicine ,Low risk patient ,Antineoplastic Combined Chemotherapy Protocols ,Medicine and Health Sciences ,Overall survival ,Registries ,Disease free survival ,Child ,MOLECULAR RESPONSE ,CHRONIC MYELOGENOUS LEUKEMIA ,Myeloid leukemia ,Hematology ,Register ,Prognosis ,Acute graft versus host disease ,Chronic Myeloid Leukemia ,Imatinib ,Protein Tyrosine Kinase Inhibitor ,Leukemia ,Treatment Outcome ,Antineoplastic agent ,030220 oncology & carcinogenesis ,Child, Preschool ,Cohort ,Disease Progression ,Female ,Infection ,medicine.drug ,Human ,Adult ,medicine.medical_specialty ,2904 CML PATIENTS ,Adolescent ,Prognosi ,Long term survival score ,Alpha interferon ,Hemoglobin blood level ,Major clinical study ,IMATINIB ,Disease-Free Survival ,Article ,Follow-Up Studie ,Spleen size ,03 medical and health sciences ,EUROPEAN LEUKEMIANET ,Median follow-up ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Disease exacerbation ,Mortality ,Survival rate ,EUTOS score ,Cancer prognosis ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Infant ,Follow up ,medicine.disease ,Prognostic discrimination ,YOUNGER PATIENTS ,CHRONIC GRANULOCYTIC-LEUKEMIA ,RANDOMIZED CML ,Cancer survival ,High risk patient ,POPULATION-BASED REGISTRY ,Leukocyte count ,Preschool child ,Immunology ,Progression free survival ,School child ,INTERFERON-ALPHA ,business ,030215 immunology ,Chronic myelogenous leukemia ,Follow-Up Studies - Abstract
The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression and/or death (whichever came first) occurred in 23 patients. For the entire cohort of patients the 5-year progression-free survival rate was 92% (95% CI: 87%-94%) and the 5-year survival accounting for chronic myeloid leukemia deaths was 97% (95% CI: 94%-99%). Of the 309 patients allocated to low (n=199), intermediate (n=68) and high (n=42) risk groups by the EUTOS Long-Term Survival score, events (progression and/or death) occurred in 6.0%, 8.8% and 26.2%, respectively. Estimates of the 5-year progression-free survival rates according to these three risk groups were 96% (95% CI: 92%-98%), 88% (95% CI: 76%-95%) and 67% (95% CI: 48%-81%), respectively. Differences in progression-free survival according to these risk groups were highly significant (P
- Published
- 2017
21. Quinoides and VEGFR2 TKIs influence the fate of hepatocellular carcinoma and its cancer stem cells† †The authors declare no competing interests. ‡ ‡Electronic supplementary information (ESI) available. See DOI: 10.1039/c6md00392c
- Author
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Gilles Hanquet, Steve Lanners, Loïc Jeanmart, Peter Šramel, Deniz Cansen Kahraman, Rengul Cetin-Atalay, Andrej Boháč, Laboratoire d'innovation moléculaire et applications (LIMA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie moléculaire (LCM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Substances naturelles/chimie moléculaire, Université Louis Pasteur - Strasbourg I-Ecole européenne de chimie, polymères et matériaux [Strasbourg]-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Unclassified drug ,VEGF receptors ,Pharmaceutical Science ,Drug structure ,Cancer cell ,IC50 ,Bioinformatics ,Biochemistry ,Gene ,0302 clinical medicine ,SYNCAT ,Epithelial cell adhesion molecule ,Quinoide ,Drug Discovery ,Cytotoxic T cell ,Medicine ,CD133 antigen ,media_common ,Protein p53 ,biology ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,Sorafenib ,Liver cell carcinoma ,3. Good health ,Chemistry ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Molecular Medicine ,Drug mechanism ,medicine.drug ,Human ,Drug ,Drug cytotoxicity ,Tumour heterogeneity ,media_common.quotation_subject ,Cell subpopulation ,Beta catenin ,Concentration response ,Cell population ,03 medical and health sciences ,Drug synthesis ,Cancer stem cell ,Drug approval ,Vimentin ,TP53 gene ,Protein tyrosine kinase inhibitor ,neoplasms ,Antineoplastic activity ,Pharmacology ,business.industry ,Organic Chemistry ,Thy 1 antigen ,Vasculotropin receptor 2 ,medicine.disease ,digestive system diseases ,Drug efficacy ,030104 developmental biology ,Human cell ,Cancer research ,biology.protein ,Protein expression ,Transcription factor ,business ,Epithelial mesenchymal transition - Abstract
Bioactivities of quinoides 1-5 and VEGFR2 TKIs 6-10 in hepatocellular cancer (HCC) and cancer stem cells (HCSCs) were studied. The compounds exhibited IC50 values in μM concentrations in HCC cells. Quinoide 3 was able to eradicate cancer stem cells, similar to the action of the stem cell inhibitor DAPT. However, the more cytotoxic VEFGR TKIs (IC50: 0.4-3.0 μM) including sorafenib, which is the only FDA approved drug for the treatment of HCC, enriched the hepatocellular cancer stem cell population by 2-3 fold after treatment. An aggressiveness factor (AF) was proposed to quantify the characteristics of drug candidates for their ability to eradicate the CSC subpopulation. Considering the tumour heterogeneity and marker positive cancer stem cell like subpopulation enrichment upon treatments in patients, this study emphasises the importance of the chemotherapeutic agent choice acting differentially on all the subpopulations including marker-positive CSCs.
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- 2016
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22. Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review
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Boussios, Stergios, Seraj, E., Zarkavelis, George, Petrakis, Dimitrios, Kollas, Aristomenes, Kafantari, Aikaterini, Assi, A., Tatsi, K., Pavlidis, Nicholas, Pentheroudakis, George, Pavlidis, Nicholas [0000-0002-2195-9961], Pentheroudakis, George [0000-0002-6632-2462], Boussios, Stergios [0000-0002-2512-6131], and Zarkavelis, George [0000-0001-5961-2237]
- Subjects
Oncology ,Cancer therapy ,Alkylating agent ,medicine.medical_treatment ,Cytotoxic t lymphocyte antigen 4 antibody ,Cancer immunotherapy ,Gimeracil plus oteracil potassium plus tegafur ,Review ,Gene ,Cervix ,Metastasis ,0302 clinical medicine ,Squamous cell carcinoma ,Pathology ,Treatment outcome ,Platinum compounds ,Mammalian target of rapamycin inhibitor ,Bevacizumab ,Vincristine ,Molecularly targeted therapy ,030220 oncology & carcinogenesis ,Human ,medicine.medical_specialty ,Practice guideline ,Uterine cervical neoplasms ,Paclitaxel ,Mitomycin ,Adenocarcinoma ,Altretamine ,03 medical and health sciences ,Bleomycin ,Cytotoxic t lymphocyte antigen 4 ,Vinorelbine tartrate ,Humans ,Ifosfamide ,Neoplasms, Squamous Cell ,Food and drug administration ,Protein tyrosine kinase inhibitor ,Cancer recurrence ,Targeted agents ,Cisplatin ,Lymph node metastasis ,Epidermal growth factor receptor ,Somatic mutation ,medicine.disease ,030104 developmental biology ,0301 basic medicine ,Vinca alkaloid ,Antimetabolite ,Virus oncogene ,Uterine Cervical Neoplasms ,Platinum Compounds ,Recurrence ,Neoplasms ,Cancer vaccine ,Recurrent disease ,Overall survival ,Cervical cancer ,Platinum derivative ,Platinum complex ,Mammalian target of rapamycin ,Hematology ,Programmed death 1 receptor ,Dna topoisomerase inhibitor ,Treatment Outcome ,Cancer radiotherapy ,Trend study ,Female ,Uterine cervix cancer ,medicine.drug ,Quality of life ,Paraaortic lymph node ,Pemetrexed ,Vinorelbine ,Pi3kca gene ,Internal medicine ,Advanced cancer ,medicine ,Drug approval ,Chemotherapy ,Pentoxifylline ,Vasculotropin ,business.industry ,United states ,Squamous cell ,Cancer ,Taxane derivative ,Gemcitabine ,Surgery ,Drug efficacy ,Quality of Life ,Topotecan ,Drug treatment failure ,business ,Unindexed drug - Abstract
Background Cervical cancer is the fourth most common cancer affecting women worldwide. Despite advances in screening and human papillomavirus (HPV) vaccination, a significant number of women present with or develop advanced disease. Palliative platinum-based chemotherapy (CT) is the standard first-line treatment for metastatic/recurrent cervical cancer. The prognosis remains poor and effective second line options are urgently needed. Methods We searched the English-language medical literature as well as relevant guideline databases, published from January 1981 to December 2015 and identified publications related to cervical cancer and its therapies. Our effort was to highlight the available treatment options in the setting of recurrent/metastatic disease. Results Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease after platinum failure is still problematic. Overall, there is a trend in terms of longer overall survival (OS) and better quality of life for the combination of cisplatin/paclitaxel (PC) as compared to the doublets of cisplatin/topotecan (TC), cisplatin/vinorelbine (VC), and cisplatin/gemcitabine (GC). Currently available single agents beyond first-line platinum-based therapy have limited efficacy in this setting and include topoisomerase inhibitors, vinca alkaloids, taxanes, alkylating agents and antimetabolites. Several targeted therapies have demonstrated activity in advanced cervical cancer. Bevacizumab has been evaluated in a phase III trial using doublets of cisplatin with paclitaxel or topotecan and has been approved in the first-line setting by the U. S. Food and Drug Administration. Selective targeting of angiogenic kinases by tyrosine kinase inhibitors (TKIs) may represent a novel therapeutic tool in this setting, but its use alone or in combination with CT is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Development of the immune checkpoint programmed cell death 1 (PD-1) and T-lymphocyte–associated molecule-4 (CTLA-4) inhibitors have been of considerable interest, leading to ongoing phase II studies in patients with advanced cervical cancer. Conclusions Progress in the management of recurrent and advanced cervical cancer patients has been slow and restricted to palliative intent. These patients should be considered for clinical trials of novel targeted agents and/or immunotherapy. © 2016 Elsevier Ireland Ltd 108 164 174
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- 2016
23. Outcomes with frontline nilotinib treatment in Turkish patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase
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Osman Ilhan, Rıdvan Ali, Zafer Baslar, Ibrahim C. Haznedaroglu, Orhan Ayyildiz, Diyar Z. Akkaynak, Ugur Ozbek, Leylagül Kaynar, Mehmet Sönmez, Demet Aydin, Akif Selim Yavuz, Bülent Ündar, Ilkiz M. Dag, Mustafa Pehlivan, Güray Saydam, Birol Guvenc, Olga Meltem Akay, Simten Dagdas, Çukurova Üniversitesi, Uludağ Üniversitesi/Tıp Fakültesi/Dahiliye Anabilim Dalı., Ali, Rıdvan, and Ege Üniversitesi
- Subjects
Male ,Pyrimidine derivative ,Peripheral occlusive artery disease ,Antagonists and inhibitors ,Treatment response ,Tyrosine-kinase inhibitor ,0302 clinical medicine ,tyrosine kinase inhibitor ,Antineoplastic agents ,Clinical endpoint ,Medicine ,Pharmacology (medical) ,Treatment outcome ,Drug safety ,Philadelphia Chromosome Positive ,Fusion proteins, bcr-abl ,General Medicine ,Amn107 ,Multicenter study ,Chronic Myeloid Leukemia ,Imatinib ,Protein Tyrosine Kinase Inhibitor ,Clinical trial ,Cholesterol ,Antineoplastic agent ,030220 oncology & carcinogenesis ,Interferon ,Cancer chemotherapy ,Treatment indication ,Human ,medicine.medical_specialty ,Early molecular response ,Protein kinase inhibitors ,Phosphate ,Cancer mortality ,Major clinical study ,Side effect ,Triacylglycerol ,Article ,Treatment duration ,03 medical and health sciences ,Alkaline phosphatase ,Humans ,Adverse effect ,nilotinib ,Aged ,Pharmacology ,Pharmacology & pharmacy ,Upper respiratory tract infection ,Follow up ,Leukopenia ,BCR-ABL1 ,Influenza ,ComputingMethodologies_PATTERNRECOGNITION ,Triacylglycerol lipase ,Hyperglycemia ,Immunology ,4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide ,Alkaline phosphatase blood level ,Heart infarction ,Survival ,Blast cell crisis ,Amylase blood level ,Imatinib-resistant ,Phosphate blood level ,Turkey (republic) ,BCR ABL protein ,hemic and lymphatic diseases ,Middle aged ,Cerebrovascular disease ,Drug withdrawal ,Follow-up ,breakpoint cluster region ,Myeloid leukemia ,Anemia ,molecular response ,Triacylglycerol blood level ,ComputingMilieux_MANAGEMENTOFCOMPUTINGANDINFORMATIONSYSTEMS ,Cholesterol blood level ,Protein kinase inhibitor ,Hypertension ,Female ,Alanine aminotransferase blood level ,Leukemia, myelogenous, chronic, BCR-ABL positive ,InformationSystems_MISCELLANEOUS ,Chronic myelogenous leukemia ,medicine.drug ,Cessation ,Adult ,Neutropenia ,medicine.drug_class ,Ischemic heart disease ,Newly diagnosed ,Rating scale ,chronic myeloid leukemia ,Internal medicine ,Rash ,Alpha plus cytarabine ,Prospective study ,Phase 2 clinical trial ,Bilirubin blood level ,business.industry ,Pruritus ,ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS ,Amylase ,Bilirubin ,Hair loss ,Philadelphia 1 chromosome ,Thrombocytopenia ,Triacylglycerol lipase blood level ,Drug efficacy ,Outcome assessment ,Pyrimidines ,Young adult ,Nilotinib ,Alanine aminotransferase ,business ,Prospective studies ,Constipation ,030215 immunology - Abstract
PubMed ID: 27501474, Objective: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with chronic myeloid leukemia in chronic phase (CML-CP). This study was the first prospective evaluation of the efficacy and safety of nilotinib in Turkish patients with newly diagnosed CML-CP. The primary endpoint of the study was the rate of major molecular response (MMR; BCR-ABL1 ? 0.1% on the International Scale [BCR-ABL1IS]) by 12 months. Methods: Patients with newly diagnosed CML-CP were treated with nilotinib 300 mg twice daily. This analysis was based on the first 12 months of follow-up in a 24-month study. Results and Conclusions: Of 112 patients enrolled, 66.1% (80% CI, 59.7–72.0%) achieved MMR and 22.3% achieved a deep molecular response of MR4.5 (BCR-ABL1IS ? 0.0032%) by 12 months. During the first year of treatment, 1 patient progressed to blast crisis and 2 patients died. Safety results were consistent with previous studies. Most adverse events (AEs) were grade 1/2. Most frequently reported nonhematologic AEs of any grade were elevations in bilirubin, alanine aminotransferase, and triglycerides. These results support the use of nilotinib 300 mg twice daily as a standard-of-care treatment option for patients with newly diagnosed CML-CP. © 2016 Informa UK Limited, trading as Taylor & Francis Group., Novartis Pharmaceuticals Corporation, This study was funded by Novartis Pharmaceuticals Corporation.
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- 2016
24. RET kinase alterations in targeted cancer therapy.
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Liu X, Hu X, Shen T, Li Q, Mooers BHM, and Wu J
- Abstract
The rearranged during transfection (RET) gene encodes a protein tyrosine kinase. RET alterations by point mutations and gene fusions were found in diverse cancers. RET fusions allow abnormal expression and activation of the oncogenic kinase, whereas only a few of RET point mutations found in human cancers are known oncogenic drivers. Earlier studies of RET-targeted therapy utilized multi-targeted protein tyrosine kinase inhibitors (TKIs) with RET inhibitor activity. These multi-targeted TKIs often led to high-grade adverse events and were subject to resistance caused by the gatekeeper mutations. Recently, two potent and selective RET TKIs, pralsetinib (BLU-667) and selpercatinib (LOXO-292), were developed. High response rates to these selective RET inhibitors across multiple forms of RET alterations in different types of cancers were observed in clinical trials, demonstrating the RET dependence in human cancers harboring these RET lesions. Pralsetinib and selpercatinib were effective in inhibiting RET
V804L/M gatekeeper mutants. However, adaptive mutations that cause resistance to pralsetinib or selpercatinib at the solvent front RETG810 residue have been found, pointing to the need for the development of the next-generation of RET TKIs., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2020.)- Published
- 2020
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25. The Role of Pazopanib in Non-Clear Cell Renal Cell Carcinoma: A Systematic Review.
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Sneed GT, Lee S, Brown JN, and Hammond JM
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- Angiogenesis Inhibitors adverse effects, Carcinoma, Renal Cell mortality, Carcinoma, Renal Cell pathology, Clinical Trials as Topic, Diarrhea chemically induced, Diarrhea epidemiology, Fatigue chemically induced, Fatigue epidemiology, Humans, Hypertension chemically induced, Hypertension epidemiology, Indazoles, Kidney Neoplasms mortality, Kidney Neoplasms pathology, Progression-Free Survival, Protein Kinase Inhibitors adverse effects, Pyrimidines adverse effects, Sulfonamides adverse effects, Angiogenesis Inhibitors administration & dosage, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy, Protein Kinase Inhibitors administration & dosage, Pyrimidines administration & dosage, Sulfonamides administration & dosage
- Abstract
Pazopanib is a protein tyrosine kinase inhibitor that limits tumor growth through angiogenesis inhibition. The use of other protein tyrosine kinase inhibitors, specifically sunitinib, within non-clear cell renal cell carcinoma (nccRCC) has led to increased survival with a decreased adverse event profile. The data for the treatment of nccRCC is limited, with most studies evaluating the use of sunitinib. Therefore, the evaluation of pazopanib is of particular clinical interest in the treatment of nccRCC. The objective of this systematic review was to assess the efficacy and safety of pazopanib for nccRCC. PubMed (1946 to April 2019) and Embase (1947 to April 2019) were queried using the search term combination: protein tyrosine kinase inhibitor or pazopanib and non clear cell renal cell carcinoma or non-clear cell renal cell carcinoma. Studies evaluating clinical outcomes of pazopanib for nccRCC were included, represented by 3 retrospective cohort studies and 1 single-arm, open-label prospective study. In patients with advanced or metastatic nccRCC, treatment with pazopanib resulted in positive effects for multiple markers of efficacy, including progression-free survival, overall survival, and objective response rates. The median duration of follow-up ranged from 11.8 months to 24.4 months. Pazopanib was well-tolerated in most studies. The most commonly reported adverse events were fatigue, diarrhea, and hypertension. Pazopanib appears to be an effective and safe option for the treatment of advanced or metastatic nccRCC. Future investigation with larger randomized controlled trials is warranted to further define the role of pazopanib in patients with nccRCC., (Published by Elsevier Inc.)
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- 2019
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26. Clinical characteristics and therapeutic outcomes of elderly patients with chronic myeloid leukemia: A retrospective multicenter study
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Korkmaz, S., Dal, M.S., Berber, I., Sahin, D.G., Doğu, Mehmet Hilmi, Ayyildiz, O., and Nizam, I.
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blood toxicity ,Male ,age distribution ,protein tyrosine kinase inhibitor ,retrospective study ,very elderly ,pyrimidine derivative ,Dasatinib ,diarrhea ,gastrointestinal symptom ,thrombocytopenia ,rash ,hydroxyurea ,Turkey (republic) ,musculoskeletal pain ,antineoplastic agent ,Aged, 80 and over ,progression free survival ,protein kinase inhibitor ,Chronic myeloid leukemia ,chromosome analysis ,clinical trial ,Protein-Tyrosine Kinases ,anemia ,aged ,female ,Treatment Outcome ,priority journal ,drug withdrawal ,multicenter study (topic) ,Imatinib Mesylate ,survival rate ,overall survival ,Antineoplastic Agents ,patient compliance ,Article ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,neutropenia ,Humans ,controlled study ,drug fatality ,human ,survival time ,Protein Kinase Inhibitors ,nilotinib ,antagonists and inhibitors ,Retrospective Studies ,treatment response ,protein tyrosine kinase ,sex ratio ,major clinical study ,mortality ,clinical feature ,Elderly patients ,multicenter study ,Pyrimidines ,imatinib ,4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide ,edema - Abstract
Aims: We aimed to investigate whether older age leads to limitations in the starting dose of imatinib in daily treatment of chronic myeloid leukemia, and to determine the compliance of elderly patients with tyrosine kinase inhibitors (TKI) therapy. Methods: Data including the clinical characteristics, therapeutic outcomes and compliance with TKI therapy of elderly patients with chronic myeloid leukemia aged >65years were collected from 13 institutions in Turkey, retrospectively. Results: A total of 69 patients (27 [39%] men, 42 [61%] women) were evaluated retrospectively. The median age of the patients was 71years (range 66-85years). Of the patients, 66 (96%) were in the chronic phase and three (4.3%) were in the accelerated phase when diagnosed. A total of 63 (91.3%) patients were receiving imatinib as the first-line therapy. The initial dose of imatinib was 400mg/day in 59 patients (93.6%). Imatinib treatment induced 57 (90.5%) complete hematological responses at 3months, 29 (46%) complete cytogenetic responses at 6months and 49 (77.7%) major molecular responses at 12months. As a result, nilotinib and dasatinib were used in 14 patients as second-line therapy. Second-line TKI induced nine complete hematological responses (64.3%) at 3months, four complete cytogenetic responses (28.6%) at 12months and seven major molecular responses (50%) at 18months. A total of 56 of the patients (81.2%) are still alive. The median overall survival and progression-free survival rates were 35months (range 1-95months) and 17months (range 0.8-95months), respectively. Conclusion: Elderly patients should receive TKI according to the same guidelines that apply to younger patients. © 2014 Japan Geriatrics Society.
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- 2015
27. Clinical characteristics and therapeutic outcomes of elderly patients with chronic myeloid leukemia: A retrospective multicenter study
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Dal, Mehmet Sinan, Korkmaz, Serdal, Berber, Ilhami, Sahin, Deniz Goren, Dogu, Mehmet Hilmi, Ayyildiz, Orhan, Nizam, Ilknur, Albayrak, Murat, Esen, Ramazan, Namdaroglu, Sinem, ŞENCAN, MEHMET, AKAY, OLGA MELTEM, Hacioglu, Sibel, Yildirim, Rahsan, Eser, Ali, TOMBAK, ANIL, Pala, Cigdem, İLHAN, OSMAN, [Korkmaz, Serdal] Kayseri Educ & Res Hosp, Div Hematol, TR-38100 Kayseri, Turkey -- [Pala, Cigdem] Erciyes Univ, Dept Hematol, Kayseri, Turkey -- [Dal, Mehmet Sinan -- Ayyildiz, Orhan] Dicle Univ, Dept Hematol, Diyarbakir, Turkey -- [Berber, Ilhami -- Nizam, Ilknur] Inonu Univ, Dept Hematol, Malatya, Turkey -- [Sahin, Deniz Goren -- Akay, Olga Meltem] Osmangazi Univ, Dept Hematol, Eskisehir, Turkey -- [Dogu, Mehmet Hilmi -- Hacioglu, Sibel] Pamukkale Univ, Dept Hematol, Denizli, Turkey -- [Albayrak, Murat] Diskapi Yildirim Beyazit Educ & Res Hosp, Dept Hematol, Ankara, Turkey -- [Namdaroglu, Sinem] Ankara Oncol Educ & Res Hosp, Dept Hematol, Ankara, Turkey -- [Ilhan, Osman] Ankara Univ, Dept Hematol, Ibni Sina Hosp, TR-06100 Ankara, Turkey -- [Esen, Ramazan] Yuzuncu Yil Univ, Dept Hematol, Van, Turkey -- [Sencan, Mehmet] Cumhuriyet Univ, Dept Hematol, Sivas, Turkey -- [Yildirim, Rahsan] Ataturk Univ, Dept Hematol, Erzurum, Turkey -- [Eser, Ali] Marmara Univ, Dept Hematol, Istanbul, Turkey -- [Tombak, Anil] Mersin Univ, Dept Hematol, Mersin, Turkey, and albayrak, murat -- 0000-0003-4025-741X
- Subjects
blood toxicity ,Male ,age distribution ,protein tyrosine kinase inhibitor ,retrospective study ,very elderly ,pyrimidine derivative ,Dasatinib ,diarrhea ,gastrointestinal symptom ,thrombocytopenia ,rash ,hydroxyurea ,Turkey (republic) ,hemic and lymphatic diseases ,musculoskeletal pain ,antineoplastic agent ,Aged, 80 and over ,progression free survival ,protein kinase inhibitor ,Chronic myeloid leukemia ,chromosome analysis ,clinical trial ,Protein-Tyrosine Kinases ,anemia ,aged ,female ,Treatment Outcome ,priority journal ,drug withdrawal ,multicenter study (topic) ,Imatinib Mesylate ,survival rate ,overall survival ,Antineoplastic Agents ,patient compliance ,Article ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,neutropenia ,Humans ,controlled study ,drug fatality ,human ,survival time ,Protein Kinase Inhibitors ,nilotinib ,antagonists and inhibitors ,Retrospective Studies ,treatment response ,protein tyrosine kinase ,sex ratio ,major clinical study ,mortality ,clinical feature ,Elderly patients ,multicenter study ,Pyrimidines ,imatinib ,4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide ,Aged ,Antineoplastic Agents/*administration & dosage ,Dasatinib/therapeutic use ,Female ,Imatinib Mesylate/*administration & dosage/adverse effects ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/mortality ,Patient Compliance ,Protein Kinase Inhibitors/*administration & dosage/adverse effects ,Protein-Tyrosine Kinases/antagonists & inhibitors ,Pyrimidines/therapeutic use ,edema - Abstract
WOS: 000355733300008, PubMed ID: 25257190, AimsWe aimed to investigate whether older age leads to limitations in the starting dose of imatinib in daily treatment of chronic myeloid leukemia, and to determine the compliance of elderly patients with tyrosine kinase inhibitors (TKI) therapy. MethodsData including the clinical characteristics, therapeutic outcomes and compliance with TKI therapy of elderly patients with chronic myeloid leukemia aged >65years were collected from 13 institutions in Turkey, retrospectively. ResultsA total of 69 patients (27 [39%] men, 42 [61%] women) were evaluated retrospectively. The median age of the patients was 71years (range 66-85years). Of the patients, 66 (96%) were in the chronic phase and three (4.3%) were in the accelerated phase when diagnosed. A total of 63 (91.3%) patients were receiving imatinib as the first-line therapy. The initial dose of imatinib was 400mg/day in 59 patients (93.6%). Imatinib treatment induced 57 (90.5%) complete hematological responses at 3months, 29 (46%) complete cytogenetic responses at 6months and 49 (77.7%) major molecular responses at 12months. As a result, nilotinib and dasatinib were used in 14 patients as second-line therapy. Second-line TKI induced nine complete hematological responses (64.3%) at 3months, four complete cytogenetic responses (28.6%) at 12months and seven major molecular responses (50%) at 18months. A total of 56 of the patients (81.2%) are still alive. The median overall survival and progression-free survival rates were 35months (range 1-95months) and 17months (range 0.8-95months), respectively. ConclusionElderly patients should receive TKI according to the same guidelines that apply to younger patients. Geriatr Gerontol Int 2015; 15: 729-735.
- Published
- 2015
28. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014.
- Abstract
There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.Copyright © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.
- Published
- 2015
29. Metastatic thyroid cancer: Three extraordinary cases highlighting management principles and recent advances.
- Abstract
Aims: Thyroid cancer represents less than 1% of all human cancers. Metastatic thyroid cancer forms an even rarer entity. There have been a number of recent advances in treatment, namely in molecular profiling and targeted therapy. Method(s): We reviewed the latest literature as well as all cases of metastatic thyroid cancer managed at our institution over the past five years. We selected three cases that best highlight key management principles. Result(s): The first case is of a 27 year old Vietnamese male with metastatic follicular cancer on a background of thyroid lobectomy 7 years prior for follicular adenoma. He presented with symptomatic pulmonary and vertebral metastases. Retrospective review of the original lobectomy revealed a missed minimally invasive follicular carcinoma. He was commenced on systemic therapy with the tyrosine kinase inhibitor sorafenib, then changed to lenvatinib on progression. He was briefly transitioned to MEK inhibitor trametinib to facilitate tumour re-differentiation and sensitisation to radioactive iodine. The second case is of a BRAF mutation positive metastatic papillary thyroid cancer in a 57 year old East Timorese female. Her condition was complicated by DIC and SVC obstruction. Commencement of BRAF inhibitor vemurafenib resulted in clinical and haematological improvement allowing for discharge home. The third case is of a 28 year old Caucasian male with a new diagnosis of sporadic MEN2A syndrome. Diagnosis was made during an inpatient admission for back pain. Investigations revealed metastatic medullary thyroid cancer complicated by extensive bone metastases. Screening detected phaeochromocytoma and primary hyperparathyroidism. Radiotherapy for bone metastases was commenced and access for vandetanib was arranged, after considering cabozantinib through clinical trial. Unfortunately, he developed tumour-induced DIC and significant functional decline. He was discharged home with palliative care. Conclusion(s): All three cases high
- Published
- 2015
30. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014.
- Abstract
There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.Copyright © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.
- Published
- 2015
31. Abnormal protein tyrosine kinases associated with human haematological malignancies
- Author
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Sun Xue-mei and Lieschke, Graham J
- Published
- 2002
- Full Text
- View/download PDF
32. Cytoskeleton-associated protein tyrosine phosphorylation involved in induction of differentiation in mouse melanoma cells
- Author
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Yan, Chunhong and Han, Rui
- Published
- 1999
- Full Text
- View/download PDF
33. Synthesis, characterization, electrochemical behavior and in vitro protein tyrosine kinase inhibitory activity of the cymene-halogenobenzohydroxamato [Ru(eta(6)-cymene)(bha)Cl] complexes
- Author
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Maxim L. Kuznetsov, Armando J. L. Pombeiro, Xianmei Shang, Telma F. S. Silva, Luísa M. D. R. S. Martins, M. Fátima C. Guedes da Silva, and Qingshan Li
- Subjects
Platinum complexes ,Stereochemistry ,Redox potentials ,chemistry.chemical_element ,Ruthenium(II) complexes ,Molecular-structure ,Biochemistry ,Redox ,Coordination complex ,Inorganic Chemistry ,X-ray ,Design strategies ,Synthesis ,Ferrocene derivatives ,Materials Chemistry ,Electrochemistry ,Ruthenium(II) arene complexes ,Molecular orbital ,Physical and Theoretical Chemistry ,Protein tyrosine kinase inhibitor ,chemistry.chemical_classification ,Crystal-structures ,Chemistry ,Ligand ,Organic Chemistry ,Carbon-13 NMR ,Ruthenium ,Coordination chemistry ,Anticancer agents ,Proton NMR ,Cyclic voltammetry - Abstract
The ruthenium(II)–cymene complexes [Ru(η 6 -cymene)(bha)Cl] with substituted halogenobenzohydroxamato (bha) ligands (substituents = 4-F, 4-Cl, 4-Br, 2,4-F 2 , 3,4-F 2 , 2,5-F 2 , 2,6-F 2 ) have been synthesized and characterized by elemental analysis, IR, 1 H NMR, 13 C NMR, cyclic voltammetry and controlled-potential electrolysis, and density functional theory (DFT) studies. The compositions of their frontier molecular orbitals (MOs) were established by DFT calculations, and the oxidation and reduction potentials are shown to follow the orders of the estimated vertical ionization potential and electron affinity, respectively. The electrochemical E L Lever parameter is estimated for the first time for the various bha ligands, which can thus be ordered according to their electron-donor character. All complexes exhibit very strong protein tyrosine kinase (PTK) inhibitory activity, even much higher than that of genistein, the clinically used PTK inhibitory drug. The complex containing the 2,4-difluorobenzohydroxamato ligand is the most active one, and the dependences of the PTK activity of the complexes and of their redox potentials on the ring substituents are discussed.
- Published
- 2013
34. Sudden blastic crisis and additional chromosomal abnormalities during chronic myeloid leukemia in the imatinib era
- Author
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Fahir Özkalemkaş, Rıdvan Ali, Mutlu Karkucak, Murat Pekgöz, Hulya Ozturk Nazlioglu, Serhat Korkmaz, Tahsin Yakut, Ahmet Tunali, Ferah Budak, Vildan Ozkocaman, Tulay Ozcelik, Uludağ Üniversitesi/Tıp Fakültesi Hastanesi/İç Hastalıkları Anabilim Dalı., Uludağ Üniversitesi/Tıp Fakültesi/Genetik Anabilim Dalı., Uludağ Üniversitesi/Tıp Fakültesi/Patoloji Anabilim Dalı., Uludağ Üniversitesi/Tıp Fakültesi/Mikrobiyoloji Anabilim Dalı., Ali, Rıdvan, Özkalemkaş, Fahir, Özkocaman, Vildan, Yakut, Tahsin, Nazlıoğlu, Hülya Öztürk, Budak, Ferah Ah, Pekgöz, Murat, Korkmaz, Serhat, Karkucak, Mutlu, Özçelik, Tülay, Tunalı, Ahmet, F-4657-2014, AAH-1854-2021, and AAG-8495-2021
- Subjects
Male ,Pathology ,Bone marrow cell ,Leukocytosis ,CD33 ,Treatment response ,Piperazines ,Acute kidney failure ,Antineoplastic agents ,Medicine ,Cell structure ,Pallor ,CD34 antigen ,In situ hybridization, fluorescence ,Chronic myeloid leukemia ,Glycophorin A ,Chromosome 19 ,General Medicine ,Prognosis ,Chromosome 13 ,Chronic Myeloid Leukemia ,Imatinib ,Protein Tyrosine Kinase Inhibitor ,Chromosome 21 ,Oncology ,Microsomal aminopeptidase ,Imatinib Mesylate ,Mesylate therapy ,Human ,medicine.medical_specialty ,Article ,Treatment duration ,Transformation ,Cytogenetics ,Blastic crisis ,Case report ,Myelocytic-leukemia ,Humans ,Blast cell ,Purpura ,CD19 antigen ,CD33 antigen ,CD45 antigen ,medicine.disease ,Dyspnea ,Karyotyping ,Splenomegaly ,Blast crisis ,Surgery ,Disseminated intravascular clotting ,Fluorescence in situ hybridization ,Continuous infusion ,Myeloid ,Blast cell crisis ,Resistance ,Myelofibrosis ,Bone marrow biopsy ,BCR ABL protein ,hemic and lymphatic diseases ,Flow cytometry ,Fatigue ,Priority journal ,Staining ,CD61 antigen ,medicine.diagnostic_test ,Progression ,Cytarabine ,Myeloid leukemia ,Anemia ,Hematology ,Cytogenetic analysis ,Death ,Leukemia ,Reticulin ,medicine.anatomical_structure ,Benzamides ,Fibrinogen receptor ,Chronic-phasebcr-abl ,Leukemia, myelogenous, chronic, BCR-ABL positive ,medicine.symptom ,Chromosome aberration ,Drug dose increase ,Chronic myelogenous leukemia ,medicine.drug ,Adult ,Options ,Bone-marrow fibrosis ,Chromosome aberrations ,Leukapheresis ,Human tissue ,Tumor lysis syndrome ,Chromosome 8 ,business.industry ,Daunorubicin ,Philadelphia 1 chromosome ,Thrombocytopenia ,Pyrimidines ,Leukocyte count ,Cell infiltration ,Bone marrow ,Cytogenetic response ,business - Abstract
Imatinib has shown significant clinical and cytogenetic success in the treatment of chronic myeloid leukemia. Although resistance has been observed in a proportion of patients, sudden blastic crisis is a rare event during imatinib therapy. We describe a 24-year-old male patient with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase who developed sudden blastic crisis in the 24th month of imatinib therapy, with loss of complete cytogenetic response. At this time, the patient had splenomegaly, severe anemia, thrombocytopenia, and leukocytosis. Bone marrow aspirate revealed the presence of massive blastic infiltration with myeloid morphology. Flow cytometric analysis of the bone marrow cells showed positivity for CD45, CD34, CD13, CD33, CD19, CD41, C1361, and glycophorin-A. Trephine biopsy specimens showed 100% cellular marrow with diffuse infiltrate by blasts. A reticulin stain of the bone marrow biopsy section demonstrated severe diffuse fibrosis. Cytogenetic analysis by fluorescence in situ hybridization (FISH) revealed that 92% of the cells were positive for the BCR/ABL fusion signal and had increased copy numbers for chromosomes 8,13,19, and 21. The patient's prognosis was unfavorable. In conclusion, chronic myeloid leukemia remains complex and includes unanswered questions. The presented case with a rare event during imatinib therapy highlights the need for the continued monitoring of residual disease and the development of strategies to eliminate residual leukemia cells in patients showing a complete cytogenetic response. Novartis İlaç
- Published
- 2009
35. Renal carcinoma with inferior vena cava tumour thrombus: An Australian experience.
- Abstract
Introduction: Renal cell carcinoma is known to extend into the IVC in 4-10% of cases.1-3 Despite the technical difficulty, cytoreductive nephrectomy has a role in palliation and may increase survival. We present a retrospective, multi-institution case series of patients undergoing radical nephrectomy and IVC thrombectomy. Material(s) and Method(s): We conducted a retrospective review of the medical records of patients undergoing a radical nephrectomy with caval thrombectomy performed by three uro-oncology units from June 1997 to June 2011. Patient demographics, thrombus extension, tumour size, length of stay, blood loss and complications were recorded. Outcome measures were based on disease progression and patient status at time of follow-up. Result(s): 29 patients were identified with 18 males and 11 females. The male mean age was 54, the female mean age was 63, and the overall mean age was 58 years. The patients were classified according to Neves score. 14 patients had Neves classification of I, 8 Neves II, 2 Neves III, and 5 Neves IV. Mean tumour size was 103.9mm (range 25-180). Mean blood loss was 1580mL (range 90-8500). Mean operative time (n=22) was 180 minutes (range 70-390). Mean LOS (n=18) was 8.8 days (range 5-22). 31% of patients had a positive surgical margin. Complication and follow-up data was limited. Complication data was available for 9 patients. There was one grade V complication, one IVb, one IIIa, six II, and one grade I complication. Followup data was available for 15 patients. Of these the mean survival time post operatively was 17.7 months (range 3-90) Conclusion(s): Despite the invasive nature of radical nephrectomy with caval thrombectomy, blood loss, LOS and complication rates are acceptable. Mean survival post surgery of 17.7 months will likely increase in the Tyrosine Kinase Inhibitor era. However, one must consider the physiological status of the patient prior to embarking on surgical intervention.
- Published
- 2012
36. Renal carcinoma with inferior vena cava tumour thrombus: An Australian experience.
- Abstract
Introduction: Renal cell carcinoma is known to extend into the IVC in 4-10% of cases.1-3 Despite the technical difficulty, cytoreductive nephrectomy has a role in palliation and may increase survival. We present a retrospective, multi-institution case series of patients undergoing radical nephrectomy and IVC thrombectomy. Material(s) and Method(s): We conducted a retrospective review of the medical records of patients undergoing a radical nephrectomy with caval thrombectomy performed by three uro-oncology units from June 1997 to June 2011. Patient demographics, thrombus extension, tumour size, length of stay, blood loss and complications were recorded. Outcome measures were based on disease progression and patient status at time of follow-up. Result(s): 29 patients were identified with 18 males and 11 females. The male mean age was 54, the female mean age was 63, and the overall mean age was 58 years. The patients were classified according to Neves score. 14 patients had Neves classification of I, 8 Neves II, 2 Neves III, and 5 Neves IV. Mean tumour size was 103.9mm (range 25-180). Mean blood loss was 1580mL (range 90-8500). Mean operative time (n=22) was 180 minutes (range 70-390). Mean LOS (n=18) was 8.8 days (range 5-22). 31% of patients had a positive surgical margin. Complication and follow-up data was limited. Complication data was available for 9 patients. There was one grade V complication, one IVb, one IIIa, six II, and one grade I complication. Followup data was available for 15 patients. Of these the mean survival time post operatively was 17.7 months (range 3-90) Conclusion(s): Despite the invasive nature of radical nephrectomy with caval thrombectomy, blood loss, LOS and complication rates are acceptable. Mean survival post surgery of 17.7 months will likely increase in the Tyrosine Kinase Inhibitor era. However, one must consider the physiological status of the patient prior to embarking on surgical intervention.
- Published
- 2012
37. The role of the molecular footprint of EGFR in tailoring treatment decisions in NSCLC
- Abstract
Free to read The majority of patients with non-small-cell lung cancer (NSCLC) present with advanced disease, with targeted therapies providing some improvement in clinical outcomes. The epidermal growth factor receptor (EGFR) tyrosine kinase (TK) plays an important role in the pathogenesis of NSCLC. Tyrosine kinase inhibitors (TKIs), which target the EGFR TK domain, have proven to be an effective treatment strategy; however, patient responses to treatment vary considerably. Therefore, the identification of patients most likely to respond to treatment is essential to optimise the benefit of TKIs. Tumour-associated activating mutations in EGFR can identify patients with NSCLC who are likely to have a good response to TKIs. Nonetheless, the majority of patients relapse within a year of starting treatment. Studies of tumours at relapse have demonstrated expression of a T790M mutation in exon 20 of the EGFR TK domain in approximately 50% of cases. Although conferring resistance to reversible TKIs, these patients may remain sensitive to new-generation irreversible/panerb inhibitors. A number of techniques have been employed for genotypic assessment of tumourassociated DNA to identify EGFR mutations, each of which has advantages and disadvantages. This review presents an overview of the current methodologies used to identify such molecular markers. Recent developments in technology may make the monitoring of changes in patients' tumour genotypes easier in clinical practice, which may enable patients' treatment regimens to be tailored during the course of their disease, potentially leading to improved patient outcomes.
- Published
- 2012
38. Receptor tyrosine kinases and their activation in melanoma
- Abstract
Free to read Receptor tyrosine kinases (RTKs) and their downstream signalling pathways have long been hypothesized to play key roles in melanoma development. A decade ago, evidence was derived largely from animal models, RTK expression studies and detection of activated RAS isoforms in a small fraction of melanomas. Predictions that overexpression of specific RTKs implied increased kinase activity and that some RTKs would show activating mutations in melanoma were largely untested. However, technological advances including rapid gene sequencing, siRNA methods and phospho-RTK arrays now give a more complete picture. Mutated forms of RTK genes including KIT, ERBB4, the EPH and FGFR families and others are known in melanoma. Additional over- or underexpressed RTKs and also protein tyrosine phosphatases (PTPs) have been reported, and activities measured. Complex interactions between RTKs and PTPs are implicated in the abnormal signalling driving aberrant growth and survival in malignant melanocytes, and indeed in normal melanocytic signalling including the response to ultraviolet radiation. Kinases are considered druggable targets, so characterization of global RTK activity in melanoma should assist the rational development of tyrosine kinase inhibitors for clinical use. © 2011 John Wiley & Sons A/S.
- Published
- 2011
39. The chick embryo chorioallantoic membrane as a model system for the study of tumor angiogenesis, invasion and development of anti-angiogenic agents
- Author
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Tufan, Ahmet Çevik and Satıroğlu-Tufan, Naciye Lale
- Subjects
mitogen activated protein kinase p38 ,cell migration ,kininogen ,1,4 phenylenebis(methylene)selenocyanate ,suramin derivative ,capillary ,angiopoietin receptor ,squalamine ,cytokine ,endothelium cell ,cell adhesion molecule antagonist ,transforming growth factor beta ,Neovascularization, Pathologic ,basic fibroblast growth factor antibody ,steroid ,cortisone ,protein function ,spironolactone ,retinoid ,fenretinide ,purine derivative ,carbohydrate derivative ,protamine ,anthracycline derivative ,doxorubicin ,saquinavir ,in vivo study ,ornithine decarboxylase inhibitor ,transforming growth factor alpha ,nitric oxide ,thalidomide ,metastasis ,Humans ,fibroblast growth factor 2 ,indole derivative ,gm 1474 ,standardization ,prothrombin ,vasculotropin ,goniodomin A ,indinavir ,scoring system ,homocysteine ,arylsulfatase inhibitor ,assay ,stromelysin ,protein family ,cyclosporin ,cell proliferation ,monoclonal antibody ,validation process ,ruthenium red derivative ,platelet derived growth factor ,kininostat ,alpha cyclodextrin ,scatter factor ,amiloride ,endostatin ,protein tyrosine kinase inhibitor ,Drug Evaluation, Preclinical ,vasculotropin antibody ,Angiogenesis Inhibitors ,Chick Embryo ,heparin ,apomorphine ,matrix metalloproteinase inhibitor ,protamine sulfate ,kininogen derivative ,Chorioallantoic Membrane ,angiogenesis ,metastatin ,Neoplasms ,cell growth ,vasculotropin receptor 2 ,motuporanine ,bleomycin ,tamoxifen ,morphometrics ,angiogenin antibody ,apoptosis ,thrombocyte factor 4 ,unclassified drug ,hyaluronic acid binding protein ,tumor growth ,heparan sulfate ,titanocene dichloride ,cancer invasion ,alpha thymosin peptide ,vasculotropin diphtheria toxin conjugate ,review ,somatostatin ,somatostatin derivative ,interleukin 2 ,Models, Biological ,angiotensinogen derivative ,peptide derivative ,chorioallantois ,organ culture ,pentosan polysulfate ,microsomal aminopeptidase inhibitor ,tumor vascularization ,fibroblast growth factor ,mesoderm ,sulindac ,drug mechanism ,Animals ,Neoplasm Invasiveness ,cell viability ,suramin ,cell culture ,angiostatin ,model ,nonhuman ,DNA synthesis ,proteasome inhibitor ,cost effectiveness analysis ,embryo development ,acetylsalicylic acid ,fetus membrane ,u 995 ,thymidine phosphorylase inhibitor ,angiogenesis inhibitor ,angiotensinogen ,beta cyclodextrin ,heparanase inhibitor ,chemokinesis - Abstract
Angiogenesis, the formation of new blood vessels, is essential for tumor growth, progression and metastasis. The development of agents that target tumor vasculature is ultimately dependent on the availability of appropriate preclinical screening assays. The chorioallantoic membrane (CAM) assay is well established and widely used as a model to examine angiogenesis, and anti-angiogenesis. This review 1) summarizes the currently used angiogenesis assays and the importance of CAM model among them; 2) summarizes the current knowledge about the development and structure of the CAM's capillary bed; 3) reports findings regarding the role played by molecular signaling pathways in angiogenesis process; 4) discusses the use, advantages and limitations of the CAM as a model for studying tumor angiogenesis and invasiveness, as well as development of angiogenic and/or anti-angiogenic agents; 5) discusses the importance of standardization of the major methodologies for all aspects of the use of the CAM in angiogenesis-related studies; 6) and finally, summarizes major findings regarding the agents developed by the use of CAM model in the study of tumor angiogenesis, invasion and development of anti-angiogenic agents. © 2005 Bentham Science Publishers Ltd.
- Published
- 2005
40. Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo
- Subjects
Male ,Vascular Endothelial Growth Factor A ,Biomedical Research ,protein tyrosine kinase inhibitor ,Messenger ,beta galactosidase ,Gene Expression ,animal cell ,Mice ,Ischemia ,angiography ,pain ,Amputation ,Myoglobin ,messenger RNA ,adenovirus vector ,Gene Therapy ,Skeletal ,RNA analysis ,Middle Aged ,semaxanib ,Muscle ,Female ,animal experiment ,Genetic Vectors ,Muscle Fibers ,Adenoviridae ,in vivo study ,angina pectoris ,vascularization ,Animals ,Humans ,controlled study ,muscle ischemia ,gastrocnemius muscle ,drug inhibition ,skeletal muscle ,Physiologic ,Biology ,protein expression ,mouse ,Neovascularization ,Aged ,nonhuman ,vasculotropin ,muscle function ,animal model ,capillary density ,Capillaries ,vasculotropin A ,Peripheral vascular disease ,myotube ,RNA ,Angiogenesis ,Vascular endothelial growth factor - Abstract
Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography, is weak. In this study, we report an angiogenesis-independent effect of VEGF on ischemic skeletal muscle, ie, upregulation of myoglobin after VEGF treatment. Mice received intramuscular injection with adenoviral VEGF-A or either adenoviral LacZ or PBS as control, followed by surgical induction of acute hindlimb ischemia at day 3. At day 6, capillary density was increased in calf muscle of Ad. VEGF-treated versus control mice (P
- Published
- 2004
41. Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo
- Author
-
Weel, V. van, Deckers, M.M.L., Grimbergen, J.M., Leuven, K.J.M. van, Lardenoye, J.W.H.P., Schlingemann, R.O., Nieuw Amerongen, G.P. van, Bockel, J.H. van, Hinsbergh, V.W.M. van, Quax, P.H.A., and Gaubius Instituut TNO
- Subjects
Male ,Vascular Endothelial Growth Factor A ,Biomedical Research ,protein tyrosine kinase inhibitor ,beta galactosidase ,Gene Expression ,animal cell ,Mice ,Ischemia ,angiography ,pain ,Amputation ,Myoglobin ,messenger RNA ,adenovirus vector ,Gene Therapy ,RNA analysis ,Middle Aged ,semaxanib ,Female ,animal experiment ,Genetic Vectors ,Neovascularization, Physiologic ,Muscle Fibers ,Adenoviridae ,in vivo study ,angina pectoris ,vascularization ,Animals ,Humans ,controlled study ,muscle ischemia ,gastrocnemius muscle ,RNA, Messenger ,drug inhibition ,skeletal muscle ,Muscle, Skeletal ,Biology ,protein expression ,mouse ,Aged ,nonhuman ,vasculotropin ,muscle function ,animal model ,capillary density ,Capillaries ,vasculotropin A ,Peripheral vascular disease ,myotube ,Angiogenesis ,Vascular endothelial growth factor - Abstract
Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization, as evaluated by angiography, is weak. In this study, we report an angiogenesis-independent effect of VEGF on ischemic skeletal muscle, ie, upregulation of myoglobin after VEGF treatment. Mice received intramuscular injection with adenoviral VEGF-A or either adenoviral LacZ or PBS as control, followed by surgical induction of acute hindlimb ischemia at day 3. At day 6, capillary density was increased in calf muscle of Ad. VEGF-treated versus control mice (P
- Published
- 2004
42. Imatinib and Pregnancy
- Author
-
Vildan Ozkocaman, Fahir Özkalemkaş, Rıdvan Ali, Tulay Ozcelik, Atilla Ozkan, Uludağ Üniversitesi/Tıp Fakültesi/Hematoloji Anabilim Dalı/İç Hastalıkları Anabilim Dalı., Ali, Rıdvan, Özkalemkaş, Fahir, Özçelik, Tülay, Özkocaman, Vildan, Özkan, Atilla, AAH-1854-2021, and AAG-8495-2021
- Subjects
Male ,Oncology ,Cancer Research ,Letter ,Pyrimidine derivative ,Abortion ,Piperazines ,Drug antagonism ,Teratogenicity ,Pregnancy ,hemic and lymphatic diseases ,Antineoplastic agents ,Cell differentiation ,Medicine ,Thrombocythemia ,Protein tyrosine kinase ,Cell proliferation ,Chemically induced disorder ,Priority journal ,Chronic myeloid leukemia ,Pregnancy trimesters ,Protein-tyrosine kinases ,Leukemia ,Teratogens ,Antineoplastic agent ,Female ,Abnormalities ,Human ,medicine.drug ,Adult ,medicine.medical_specialty ,Teratogenic agent ,Abortion, spontaneous ,MEDLINE ,Leukemia, myeloid, chronic ,Myelogenous ,Pregnancy complication ,Internal medicine ,Humans ,Animals ,Pregnancy Trimesters ,neoplasms ,Protein tyrosine kinase inhibitor ,Piperazine derivative ,Spontaneous abortion ,Animal ,business.industry ,Imatinib ,Note ,medicine.disease ,Chronic Myeloid Leukemia ,Pyrimidines ,Imatinib mesylate ,Pregnancy complications, neoplastic ,Congenital malformation ,business - Abstract
We read with great interest the article by Ault et al1 in a recent issue of Journal of Clinical Oncology, describing the results of pregnancy among patients with chronic myeloid leukemia (CML) treated with imatinib. We would like to add some points and bring attention to some questions concerning imatinib and pregnancy. Tyrosine kinases (TKs) are one of the most critical groups of signaling molecules for the cellular regulation of proliferation, differentiation, survival, function, and motility, and various tumors overexpress TKs, leading to uncontrolled mitogenic signals to the neoplastic cells. Imatinib (Gleevec or Glivec; Novartis, Basel, Switzerland) is a small-molecule tyrosine kinase inhibitor active against BCR-ABL, c-ABL, ARG, PDGF-r, and c-KIT.2 Although imatinib has been used primarily for cancers such as CML, use of imatinib has demonstrated that tyrosine kinase inhibitors can have a wide therapeutic window and heralds the era of targeted cancer and noncancer disease therapy. Information about the effects of drugs on the developing embryo is derived primarily from animal experiments and case reports describing the outcomes of pregnancies complicated with drug. Some drugs can be teratogenic in some animal species, but not in humans. In preclinical studies imatinib was found to be teratogenic in rats, but not in rabbits, and impaired spermatogenesis was observed in rats, dogs, and monkeys; however, there was no evidence that imatinib was genotoxic. These observations lead to concerns that men treated with imatinib may have reduced sperm counts. Clinical experience has not shown this to be true because male patients who were receiving treatment of imatinib were partners in 18 pregnancies and four healthy infants. Owing to teratogenicity data in rats (causing exencephaly or encephalocele, and absent or reduced frontal and absent parietal bones), it is recommended that women treated with imatinib be aware of the potential teratogenicity of imatinib, and effective contraception should be used during imatinib therapy to prevent pregnancy.2 Hensley and Ford2 reported 26 pregnancies (15 in clinical trials, 11 in nonclinical trials) among women taking imatinib. Most of the patients opted for elective therapeutic abortions, and only three patients carried their pregnancies to term. Two infants were healthy, and one infant had hypospadias. Recently, eight patients with CML who became pregnant while receiving imatinib therapy were reported from different areas of the world.3-7 All of the fetuses had been exposed to imatinib during the first trimester, and four fetuses have also been exposed to imatinib during the second and third trimesters. Six of the reported eight pregnancies proceeded to term with healthy infants, and two were terminated with unsatisfactory outcomes—one had spontaneous abortion4 and the other had a dead fetus with meningocele.7 More recently, Ault et al1 reported their experience on 19 pregnancies involving 18 patients (10 female and eight male patients) who conceived while receiving imatinib for the treatment of CML. Three pregnancies (involving two female patients and one male patient) ended in spontaneous abortion, and one patient had an elective abortion. All other pregnancies were uneventful. Two of 16 infants had minor abnormalities at or shortly after birth (hypospadias in one and rotation of small intestine in another) that were surgically repaired.
- Published
- 2006
43. Nitric oxide production by macrophages stimulated by antigen-binding T-cell factors
- Author
-
Redegeld, F.A., Heijdra, B., Knippels, M.-C., Garssen, J., Nijkamp, F.P., Sub Immunopharmacology, Sub Biology Education begr. 01-01-2013, Sub General Pharmacology, and Biology Education
- Subjects
Lipopolysaccharides ,Picryl chloride factor ,Indoles ,protein tyrosine kinase inhibitor ,T-Lymphocytes ,animal cell ,Picryl Chloride ,Picryl chloride ,Maleimides ,chemistry.chemical_compound ,Mice ,1 fluoro 2,4 dinitrobenzene ,T lymphocyte ,Immunology and Allergy ,antigen binding ,Enzyme Inhibitors ,conference paper ,Protein Kinase C ,Lymphokines ,biology ,Kinase ,nitric oxide synthase ,lipopolysaccharide ,Protein-Tyrosine Kinases ,Genistein ,1 fluoro 2 ,Cell biology ,Nitric oxide synthase ,Biochemistry ,priority journal ,Signal transduction ,Tyrosine kinase ,signal transduction ,culture medium ,Immunology ,binding protein ,protein kinase C inhibitor ,contact sensitivity ,Nitric Oxide ,Nitric oxide ,Cell Line ,Animals ,controlled study ,Antigens ,4 dinitrobenzene ,nitrite ,Protein kinase C ,mouse ,nonhuman ,Antigen-specific T-cell factor ,Binding protein ,Macrophages ,molecular weight ,Macrophage Activation ,Isoflavones ,chemistry ,biology.protein ,Dinitrofluorobenzene - Abstract
Contact sensitivity to small molecular weight compounds is accompanied by the production of antigen-specific T-cell factors (TCF) shortly after skin application of the sensitizing agents. In this study, we show that macrophages can be activated by these TCF to generate large amounts of nitric oxide (NO). Incubation of the murine macrophage cell line J774 for 24 h with TCF raised against dinitrofluorobenzene (DNFB) or picryl chloride (PCL) resulted in a nitrite accumulation in the culture medium. Priming of J774 with rIFN-gamma synergistically enhanced stimulation of NO synthesis by DNFB-F and PCL-F. A possible contribution of lipopolysaccharide (LPS) as a contaminant of the TCF was excluded. The enhanced production of NO after stimulation with TCF was accompanied with an increased expression of inducible NO synthase. Inclusion of inhibitors of protein tyrosine kinase and protein kinase C inhibited the TCF-induced NO production by macrophages, indicating the involvement of both protein kinases in the signaling pathway activated by TCF. Since NO is an important biological mediator with many immunoregulatory properties, our results suggest a potential role for increased NO production by macrophages in the elicitation of contact sensitivity to small molecular weight compounds.
- Published
- 1997
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