Single Oral Administration of KRN383, a Novel Flt3 Inhibitor, Induces Eradication of the Xenograft Tumor Harboring Flt3 Mutation in Mice.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2545-2545
Author(s):  
Uichi Nishiyama ◽  
Masako Ozai ◽  
Rieko Yoshioka ◽  
Tetsuya Yoshino ◽  
Yuko Ogasawara ◽  
...  
Keyword(s):  
Oral Administration ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Therapeutic Potential ◽  
Leukemia Cell ◽  
Tumor Xenograft ◽  
Leukemia Cell Line ◽  
Activating Mutations ◽  
Flt3 Inhibitor

Abstract Constitutively activating mutations of the Flt3 receptor tyrosine kinase including internal tandem duplication (ITD) mutations are the most common genetic abnormality and are associated with a poor prognosis in acute myeloid leukemia (AML) patients. Therefore, Flt3 is a potential therapeutic target in AML. We show here the results of pre-clinical studies on KRN383, a novel orally active quinoline-urea derivative. KRN383 inhibited autophosphorylation of ITD mutant (IC50=1.3nM) and wild type (IC50=0.4nM) Flt3 in the leukemia cell line MV4-11 and THP-1, respectively. KRN383 induced cell cycle arrest, apoptosis and suppression of proliferation (IC50=0.8nM) of MV4-11 in vitro. Single (80mg/kg) or consecutive (20mg/kg/d X 28d) oral administration of KRN383 induced eradication (longer than 6mo) of tumor xenograft (MV4-11) subcutaneously implanted in all nude mice. All these effects were superior to those of SU11248, a precedent Flt3 inhibitor. In addition, single (80mg/kg) administration of KRN383 prolonged the survival of SCID mice to which MOLM-13 (ITD mutant positive leukemia cell line) was intravenously transplanted. The advantage of KRN383 over SU11248 was more obvious in in vitro studies in which the inhibition of Flt3 autophosphorylation and cellular proliferation induced by transient exposure with those drugs was determined. These results indicate that KRN383 has therapeutic potential in ITD mutant positive AML. Furthermore, eradication induced by single administration of KRN383 suggests that KRN383 provides feasibility to set wide variety of clinical regimens including multi-cycle and combination therapies. In vitro activity of Ki23819, hydrochloride salt of KRN383, is also to be reported in this ASH meeting (Komeno et al.).

The Human Leukemic HL-60 Cell Line: An in Vitro Model for Cell Death Endpoint Identification

1996 ◽  
Vol 24 (4) ◽  
pp. 581-587
Author(s):  
Cristiana Zanetti ◽  
Arrnalaura Stammati ◽  
Orazio Sapora ◽  
Flavia Zucco
Keyword(s):  
Cell Death ◽  
Cell Line ◽  
In Vitro Model ◽  
Leukemia Cell ◽  
Promyelocytic Leukemia ◽  
Leukemia Cell Line ◽  
Cell Type ◽  
Vitro Model ◽  
Promyelocytic Leukemia Cell Line

The aim of this study was to investigate the endpoints related to cell death, either necrosis or apoptosis, induced by four chemicals in the promyelocytic leukemia cell line, HL-60. Cell morphology, DNA fragmentation, cytofluorimetric analysis and oxygen consumption were used to classify the type of cell death observed. In our analysis, we found that not all the selected parameters reproduced the differences observed in the cell death caused by the four chemicals tested. As cell death is a very complex phenomenon, several factors should be taken into account (cell type, exposure time and chemical concentration), if chemicals are to be classified according to differences in the mechanisms more directly involved in cell death.

Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 925-932 ◽  
Author(s):  
Michael C. Heinrich ◽  
Diana J. Griffith ◽  
Brian J. Druker ◽  
Cecily L. Wait ◽  
Kristen A. Ott ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Map Kinase ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Line ◽  
Tyrosine Kinase Activity ◽  
Sti 571

Abstract STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.

scholarly journals Human Platelets Effectively Kill K-562 Cells, a Chronic Myelogenic Leukemia Cell Line,in vitro

1990 ◽  
Vol 81 (5) ◽  
pp. 449-453 ◽  
Author(s):  
Terutaka Sagawa ◽  
Takeshi Kodama ◽  
Akio Tominaga ◽  
Mariko Okada
Keyword(s):  
Cell Line ◽  
Leukemia Cell ◽  
Human Platelets ◽  
Leukemia Cell Line ◽  
K 562 Cells

SYNTHESIS, SPECTRAL CHARACTERIZATION AND ANTICANCER EVALUATION OF NEW DIAZENYL SCHIFF BASE DERIVATIVES

INDIAN DRUGS ◽  
2017 ◽  
Vol 54 (02) ◽  
pp. 20-28
Author(s):  
P. K. N. Sarangi ◽  
◽  
J. Sahoo ◽  
S. K Paidesetty ◽  
G. P. Mohanta
Keyword(s):  
Schiff Base ◽  
Anticancer Activity ◽  
Cell Line ◽  
Leukemia Cell ◽  
Cancer Cell Line ◽  
Leukemia Cell Line ◽  
Primary Amines ◽  
Schiff Base Derivatives ◽  
Mcf 7

A series of several diazenyl Schiff base derivatives were designed and synthesized through azo coupling of diazotised primary amines with the novel synthesized Schiff base ligand (E)-N-((2-chloroquinolin-3-yl) methylene)-4-phenylthiazol-2-amine. All the synthesized compounds have been analysed by different spectral techniques such as elemental analysis, 1H NMR, FT-IR, UV-Vis and LC-MS for their structural confirmation. The above conjugates have been studied for their solvent effects by treating them with different solvents. The results of in vitro cytotoxic study of the synthesized compounds against MCF 7 (human breast cancer cell line) and K562 (Chronic Myeloid Leukemia cell line) revealed that some of the compounds show cytotoxic effect. However, the compounds (NZ)-N-(((4-bromo-3-methylphenyl) diazenyl) (2-chloroquinolin-3-yl) methylene)-4-phenylthiazol-2-amine: (5d) and 4-(((Z)-(2-chloroquinolin-3- yl)(4-phenylthiazol-2-ylimino)methyl)diazenyl)phenol (5e) showed potent cytotoxic activity in comparison to other compounds against MCF 7. Corroborating the results of anticancer activity, it is found to be observed that the compound 4- (((Z)- (2-chloroquinolin-3-yl) (4-phenylthiazol-2-ylimino)methyl) diazenyl) phenol (5e) showed excellent anticancer activity against MCF 7, which is further justified by the apoptosis study through Annexin V-FITC/PI analysis.

scholarly journals The oxidation of (−)-epigallocatechin-3-gallate inhibits T-cell acute lymphoblastic leukemia cell line HPB-ALL via the regulation of Notch1 expression

RSC Advances ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 1679-1684 ◽  
Author(s):  
Yu-Na Wang ◽  
Jing Wang ◽  
Hao-Nan Yang ◽  
Bang-Lei Zhang ◽  
Pan Zhang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Line ◽  
Hematological Malignancy ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Activating Mutations ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia Cell Line

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and commonly associated with activating mutations in the Notch1 pathway.

scholarly journals Tumor Inhibiting [1,2-Bis(fluorophenyl)ethylenediamine]platinum(II) Complexes Part II: Biological Evaluation -in vitro Studies on the P 388 D1 Leukemia Cell Line

1990 ◽  
Vol 323 (3) ◽  
pp. 133-140 ◽  
Author(s):  
Herta Reile ◽  
Richard Müller ◽  
Ronald Gust ◽  
Reiner Laske ◽  
Walter Krischke ◽  
...  
Keyword(s):  
Cell Line ◽  
Leukemia Cell ◽  
Biological Evaluation ◽  
In Vitro Studies ◽  
Leukemia Cell Line

Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 925-932 ◽  
Author(s):  
Michael C. Heinrich ◽  
Diana J. Griffith ◽  
Brian J. Druker ◽  
Cecily L. Wait ◽  
Kristen A. Ott ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Map Kinase ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Line ◽  
Tyrosine Kinase Activity ◽  
Sti 571

STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.

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