Synthesis of Cytarabine Lipid Drug Conjugate for Treatment of Meningeal Leukemia: Development, Characterization and In Vitro Cell Line Studies

2012 ◽  
Vol 8 (6) ◽  
pp. 928-937 ◽  
Author(s):  
Pravin Sharma ◽  
Brahmanand Dube ◽  
Krutika Sawant
Keyword(s):  
Cell Line ◽  
Drug Conjugate ◽  
Leukemia Development ◽  
Meningeal Leukemia

Identification of Gfi1 as a Direct Target of the Leukemogenic Fusion Protein AML1-ETO9a

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2439-2439
Author(s):  
Miao-Chia Lo ◽  
Luke F. Peterson ◽  
I-Ming Chen ◽  
Cheryl L. Willman ◽  
Dong-Er Zhang
Keyword(s):  
Cell Line ◽  
Leukemia Cell ◽  
Initiation Site ◽  
Leukemia Cell Line ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Transcriptional Initiation ◽  
Leukemia Development ◽  
Direct Target ◽  
On Chip

Abstract AML1-ETO9a (AE9a), a C-terminal splice variant of t(8;21), is highly leukemogenic in mice. Using combined gene expression and promoter occupancy (ChIP-on-chip) profiling of an AE9a induced murine AML model, we identified Gfi1, a transcriptional repressor important for neutrophil differentiation, as a direct target of AE9a. The level of Gfi1 mRNA was down-regulated following leukemia development. We further show that t(8;21) AML-M2 patient samples have lower Gfi1 mRNA levels compared to non-t(8;21) AML-M2 samples. In addition, Gfi1 protein was down-regulated in the human hematopoietic cell line U937 upon AE or AE9a expression. Two consensus AML1 sites (TGTGGT) located at positions −1750 and +405 from the Gfi1 transcriptional initiation site, respectively, are found in the proximity of the peaks of ChIP-on-chip profiling. We confirmed direct DNA binding of AE9a to these regions by ChIP assays. Furthermore, we showed that the activity of the Gfi1 promoter region −1880 to +481 is repressed by AE and AE9a in luciferase reporter assays. To address the effects of down-regulation of Gfi1 on proliferation, we overexpressed it in a primary AML1-ETO C-terminal mutant (AML1-ETOtr) leukemia cell line. Its overexpression slowed down growth and promoted apoptosis and differentiation of this cell line. In this report, we provide evidence that AE9a directly down-regulates Gfi1, thereby inhibiting hematopoietic differentiation, which may contribute to leukemia development.

scholarly journals IL3RA-Targeting Antibody–Drug Conjugate BAY-943 with a Kinesin Spindle Protein Inhibitor Payload Shows Efficacy in Preclinical Models of Hematologic Malignancies

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3464
Author(s):  
Dennis Kirchhoff ◽  
Beatrix Stelte-Ludwig ◽  
Hans-Georg Lerchen ◽  
Antje Margret Wengner ◽  
Oliver von Ahsen ◽  
...  
Keyword(s):  
Cell Line ◽  
Liver Toxicity ◽  
Xenograft Model ◽  
Hematologic Malignancies ◽  
Protein Inhibitor ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Kinesin Spindle Protein ◽  
Antibody Drug

IL3RA (CD123) is the alpha subunit of the interleukin 3 (IL-3) receptor, which regulates the proliferation, survival, and differentiation of hematopoietic cells. IL3RA is frequently expressed in acute myeloid leukemia (AML) and classical Hodgkin lymphoma (HL), presenting an opportunity to treat AML and HL with an IL3RA-directed antibody–drug conjugate (ADC). Here, we describe BAY-943 (IL3RA-ADC), a novel IL3RA-targeting ADC consisting of a humanized anti-IL3RA antibody conjugated to a potent proprietary kinesin spindle protein inhibitor (KSPi). In vitro, IL3RA-ADC showed potent and selective antiproliferative efficacy in a panel of IL3RA-expressing AML and HL cell lines. In vivo, IL3RA-ADC improved survival and reduced tumor burden in IL3RA-positive human AML cell line-derived (MOLM-13 and MV-4-11) as well as in patient-derived xenograft (PDX) models (AM7577 and AML11655) in mice. Furthermore, IL3RA-ADC induced complete tumor remission in 12 out of 13 mice in an IL3RA-positive HL cell line-derived xenograft model (HDLM-2). IL3RA-ADC was well-tolerated and showed no signs of thrombocytopenia, neutropenia, or liver toxicity in rats, or in cynomolgus monkeys when dosed up to 20 mg/kg. Overall, the preclinical results support the further development of BAY-943 as an innovative approach for the treatment of IL3RA-positive hematologic malignancies.

scholarly journals A developed antibody–drug conjugate rituximab-vcMMAE shows a potent cytotoxic activity against CD20-positive cell line

2018 ◽  
Vol 46 (sup2) ◽  
pp. 1-8 ◽  
Author(s):  
Meghdad Abdollahpour-Alitappeh ◽  
Seyed Masoud Hashemi Karouei ◽  
Majid Lotfinia ◽  
Amir Amanzadeh ◽  
Mahdi Habibi-Anbouhi
Keyword(s):  
Cytotoxic Activity ◽  
Cell Line ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

Targeted Therapy Of Acute Myeloid Leukemia By A CD117-Specific Aptamer-Drug-Conjugate

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1446-1446 ◽  
Author(s):  
Nianxi Zhao ◽  
Sung-nan Pei ◽  
Jianjun Qi ◽  
Pei Lin ◽  
Youli Zu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Targeted Therapy ◽  
Cell Line ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Remission Induction ◽  
Lymphoma Cell Line ◽  
Cell Binding ◽  
Drug Conjugate ◽  
Acute Myeloid

Abstract The current treatment paradigm for acute myeloid leukemia (AML) is remission induction chemotherapy, followed by either consolidation chemotherapy or allogeneic stem cell transplantation. As most patients diagnosed with AML are in their sixth or seventh decade of life, many are not candidates for standard remission induction chemotherapy because of the risk of toxicities, such as profound myelosuppression, life-threatening infections, and cardiotoxicity. The development of new effective and safe treatments for AML is therefore needed. The “ideal” therapy should specifically target AML tumor cells with no side-effect on normal cells. Since CD117 (c-Kit) is a transmembrane receptor on tumor cells surface and expresses in 70% cases of AML, it is a potential molecule for developing new targeted therapy. Aptamers are single-stranded oligonucleotides (DNA or RNA), which have the ability to specifically bind to their targets with high affinity. As a “chemical antibody”, aptamers can be chemically synthesized, easily conjugated with therapeutic drugs, and more importantly, less or not immunogenic. In this study, we developed single strand DNA (ssDNA) aptamer specific for CD117 by using a unique hybrid SELEX approach with both cell-selection and protein-enrichment. When sequencing the enriched ssDNA library with million reads, one dominant sequence had over 80% copies of total sequence reads. Cell binding analysis of the aptamer by flow cytometry and fluorescent microscopy (figure 1) demonstrated that, the aptamer molecule specifically bound to CD117-expressing AML cells, but did not react to CD117-negative control cells including Histiocytic lymphoma Cell line: U937, Burkitt's lymphoma cell line: CA46, Breast adenocarcinoma cell line: 468 and human prostate carcinoma cell line: LNCap. In addition, the presence of aptamers inhibited cell binding anti-CD117 antibody, indicating that aptamer targeted CD117 receptor on leukemic cells. Notably, this aptamer specifically targeted CD117-positve AML cells of clinical specimens with an identical staining pattern to that observed with anti-CD117 antibody (figure 2), indicating potential for in clinical use. For targeted therapy, an aptamer -drug-conjugate was formulated by chemical conjugation of ssDNA CD117 aptamer (Apt) to chemotherapeutic drug, Methotrexate (MTX). For treatment study, cell mixture of leukemic cells HEL (CD117+) and U937 (CD117-), which showed the same sensitivity to free MTX, were used (figure 3A). Exposure of cells to the Apt-MTX revealed that the formed aptamer-drug-conjugate specifically killed CD117 positive cells, but had no effect on the growth of the off-target cells in the same cultures. For therapeutic effect, Apt-MTX killed 60% of positive cells at as low as 10nM final concentration (figure 3B). In contrast, under the same condition, free MTX had no effect on cell growth (figure 3A). Our study demonstrated that the aptamer-drug-conjugate could be a new targeted therapeutics in addition to current antibody-drug-conjugate. Disclosures: No relevant conflicts of interest to declare.

Ultrastructure of NPC/HK1 cells heterotransplanted in athymic nude mice

1982 ◽  
Vol 40 ◽  
pp. 236-237
Author(s):  
E.C. Chew ◽  
C.L. Li ◽  
D.P. Huang ◽  
H.C. Ho ◽  
L.S. Mak ◽  
...  
Keyword(s):  
Cell Line ◽  
Nude Mice ◽  
Biopsy Specimen ◽  
Epithelial Cell Line ◽  
Present Communication ◽  
Recurrent Tumour ◽  
Athymic Nude Mice ◽  
Cell Line Establishment ◽  
Fine Structures ◽  
Well Differentiated

An epithelial cell line, NPC/HK1, has recently been established from a biopsy specimen of a recurrent tumour of the nasopharynx which was histologically diagnosed as a moderately to well differentiated squamous cell carcinoma. A definite decrease in the amount of tonofilaments and desmosomes in the NPC/HK1 cells during the cell line establishment was observed. The present communication reports on the fine structures of the NPC/HK1 cells heterotraneplanted in athymic nude mice.

Ultrastructure of Choriocarcinoma in Vitro

1969 ◽  
Vol 27 ◽  
pp. 362-363
Author(s):  
John C. Garancis ◽  
R. A. Pattillo
Keyword(s):  
Cell Line ◽  
Physiological Function ◽  
Cell System ◽  
Bewo Cell ◽  
Bewo Cells ◽  
Gestational Choriocarcinoma ◽  
Bewo Cell Line

Growth of cell system (BeWo-cell line) derived from human gestational choriocarcinoma has been established and continuously maintained in-vitro. Furthermore, it is evident from the previous studies that this cell line has retained the physiological function of the placental trophoblasts, namely the synthesis of human chorionic gonadotrophil(HCG).The BeWo cells were relatively small and possessed single nuclei, thus indicating that this cell line consists exclusively of cytotrophoblasts. In some instances cells appeared widely separated and their lateral surfaces were provided with numerous microvilli (Fig.1).

An Established Epithelial Cell Line (NPC/HK1) from a Nasopharyngeal Carcinoma - II. A Sem Study

1982 ◽  
Vol 40 ◽  
pp. 224-225
Author(s):  
Li C.L. ◽  
Chew E.C. ◽  
Huang D.P. ◽  
Ho H.C. ◽  
Mak L.S. ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Epithelial Cell ◽  
Surface Morphology ◽  
Cell Line ◽  
Epithelial Cell Line ◽  
Present Communication ◽  
Cells In Culture ◽  
Sem Study ◽  
Well Differentiated

An epithelial cell line, NPC/HK1, has recently been successfully established from a nasopharyngeal carcinoma of the moderately to well differentiated squamous type. The present communication reports on the surface morphology of the NPC/HK1 cells in culture.

Aberrant Type C Virus Production in a Cell Line Derived from Balb/3T3

1972 ◽  
Vol 30 ◽  
pp. 286-287
Author(s):  
N. Savage ◽  
A. Hackett
Keyword(s):  
Electron Microscopy ◽  
Cell Line ◽  
Leukemia Virus ◽  
Morphological Characteristics ◽  
Virus Production ◽  
Oncogenic Viruses ◽  
Endogenous Virus ◽  
Virus Particles ◽  
Moloney Leukemia Virus ◽  
A Cell

A cell line, UC1-B, which was derived from Balb/3T3 cells, maintains the same morphological characteristics of the non-transformed parental culture, and shows no evidence of spontaneous virus production. Survey by electron microscopy shows that the cell line consists of spindle-shaped cells with no unusual features and no endogenous virus particles.UC1-B cells respond to Moloney leukemia virus (MLV) infection by a change in morphology and growth pattern which is typical of cells transformed by sarcoma virus. Electron microscopy shows that the cells are now variable in shape (rounded, rhomboid, and spindle), and each cell type has some microvilli. Virtually all (90%) of the cells show virus particles developing at the cell surface and within the cytoplasm. Maturing viruses, typical of the oncogenic viruses, are found along with atypical tubular forms in the same cell.

A New Human Breast Tumor Cell Line

1975 ◽  
Vol 33 ◽  
pp. 388-389
Author(s):  
R.E. Nordquist ◽  
R.M. Wasik ◽  
P.J. Riggs ◽  
P.L. Munson ◽  
F.B. Schafer
Keyword(s):  
Electron Microscopy ◽  
Cell Line ◽  
Calf Serum ◽  
Tumor Cell Line ◽  
Electron Microscopic Examination ◽  
Epithelial Cell Line ◽  
Electron Microscopic ◽  
Fixed Tissue ◽  
Excised Tissue ◽  
Caucasian Female

An infiltrating ductal cell carcinoma was removed from the breast of a postmenopausal Caucasian female. The excised tissue was divided into three parts; one part for electron microscopy, one part for tissue culture and the remainder frozen for immunological studies.The tissue for culture was minced finely with sterile razor blades and cultured in Falcon flasks containing Eagel's MEM supplemented with 10% heat denatured fetal calf serum. The tissue for electron microscopy was fixed in 6.25% glutaraldehyde in 0.1 M PO4 buffer plus 5% sucrose and postfixed in 1% OsO4 in the same buffer. The fixed tissue was dehydrated in graded ethanol and embedded in Spurr.The tissue which was cultured began to grow out after approximately six weeks and became a continuous epithelial cell line which was designated BOT-2 (Breast Original Tumor). Electron microscopic examination revealed that these cells had epithelial characteristics, i.e. the presence of tonofilaments and well formed desmosomes.

Fish kidney cell line in response to heat shock

1992 ◽  
Vol 50 (1) ◽  
pp. 704-705
Author(s):  
Li-Chu Tung ◽  
Yung-Reui Chen ◽  
Shiu-Nan Chen ◽  
Guang-Hsiung Kuo
Keyword(s):  
Heat Shock ◽  
Cell Line ◽  
Fetal Calf Serum ◽  
Calf Serum ◽  
Uranyl Acetate ◽  
Ultrastructural Changes ◽  
Heat Shock Treatment ◽  
Acanthopagrus Schlegeli ◽  
Cacodylate Buffer ◽  
Fish Kidney

In the present study, the ultrastructural changes of BPK cells, a fibroblast-like cell line, derived from the kidney of juvenile black porgy Acanthopagrus schlegeli, under heat shock treatment are described.The BPK cells were maintained in L-15 medium supplemented with 10% fetal calf serum and 0.15 M NaCl at 28|C2. The heating was carried out in precalibrated water baths. Monolayers of cells, grown on coverslips in parafilm-sealed petri dishes were submerged under water for 30 min at 40|C treatments. Cells were fixed in 2.5% glutaraldehyde in 0.1 M cacodylate buffer supplemented with 6.6% sucrose, postfixed in 1% OsO4 and flat embedded in Spurr’s resin. Silver section were cut parallel to the substratum, stained with uranyl acetate and Reynold’s lead citrate, and examined in a Hitachi H-600 electron microscope at 75 KV.

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