Trans-Dominant Inhibition of Poly(ADP-Ribosyl)ation: A Novel Approach toward Tumor Cell Sensitization

1995 ◽  
pp. 142-147
Author(s):  
Jan-Heiner Küpper ◽  
Marcus Müller ◽  
Alexander Bürkle
Keyword(s):  
Tumor Cell ◽  
Novel Approach

scholarly journals Novel approach for detecting global epigenetic alterations associated with tumor cell aneuploidy

2007 ◽  
Vol 121 (7) ◽  
pp. 1487-1493 ◽  
Author(s):  
Wataru Habano ◽  
Tamotsu Sugai ◽  
Yu-Fei Jiao ◽  
Shin-Ichi Nakamura
Keyword(s):  
Tumor Cell ◽  
Epigenetic Alterations ◽  
Novel Approach

scholarly journals 274 CD47 x EpCAM bispecific antibody represents a novel approach for treating EpCAM overexpressing solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A297-A297
Author(s):  
Xinhua Wang ◽  
Oi Kwan Wong ◽  
Lei Shi ◽  
Qi Fei ◽  
Leonard Post ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Bispecific Antibody ◽  
Regulatory Protein ◽  
List Type ◽  
Antibody Treatment ◽  
Epcam Expression ◽  
Novel Approach ◽  
Animal Care

BackgroundCD47 conveys a ”don’t eat me” signal through the interaction with its ligand signal regulatory protein-alpha (SIRPa) on myeloid cells and blocks macrophage mediated phagocytosis. Tumor cells, which express high level of CD47, exploit this mechanism to evade from immune surveillance. CD47/SIRPa axis is an important checkpoint of innate immune system and CD47 is considered a prominent target for cancer treatment.1 However, the wide expression of CD47 on normal cells could cause antigen sink and lead to safety issues, such as anemia and thrombocytopenia. EpCAM is highly expressed in many epithelial cancers, particularly in colorectal, gastric, endometrial and lung cancers. Here we describe a novel CD47 x EpCAM bispecific antibody, which specifically targets CD47+/EpCAM+ tumors in preclinical studies.MethodsThe CD47 x EpCAM bispecific antibody was generated using novel anti-CD47 antibody and anti-EpCAM antibody. A series of in vitro assays including FACS binding, FACS-based SIRPa blocking, ADCP, RBC binding and hemagglutination were performed to characterize the CD47 x EpCAM bispecific antibody. In vivo efficacies of this bispecific antibody were evaluated in xenograft tumor models with high EpCAM and CD47 expression.ResultsCompared to monoclonal CD47 antibody, the CD47 x EpCAM bispecific antibody selectively binds to tumor cells overexpressing EpCAM. The bispecific antibody exhibited potent SIRPa blocking and antibody-dependent cellular phagocytosis (ADCP) activity on CD47+/EpCAM+ tumor cells, but not on cells lacking EpCAM expression. Compared to its parental CD47 monoclonal antibody, the EC50 of SIRPa blocking activity were improved 30–80 folds with the treatment of the CD47 x EpCAM bispecific antibody in tumor cell lines with high EpCAM expression. No significant RBC binding and RBC phagocytosis were observed upon treatment with the CD47 x EpCAM bispecific antibody. The bispecific antibody did not cause any appreciable hemagglutination with up to 1µM antibody treatment. Most importantly, the bispecific antibody demonstrated potent anti-tumor activities in in vivo solid tumor cell line-derived xenograft (CDX) models that overexpress both CD47 and EpCAM.ConclusionsOur findings suggest that the novel CD47 x EpCAM bispecific antibody selectively binds to CD47 and blocks CD47/SIRPa binding on EpCAM overexpressing tumor cells. The bispecific antibody has minimum RBC binding compared to the bivalent CD47 monoclonal antibodies. The bispecific antibody shows potent in vivo efficacy and specificity toward EpCAM positive tumor cells and represents a novel approach for treating EpCAM+ tumors.ReferencesChao M, Weissman I, Majeti R. The CD47-SIRPa pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol 2012;24(2):225–232.Ethics ApprovalThe protocol and any amendment(s) or procedures involving the care and use of animals in these animal studies were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of WuXi AppTec prior to conduct. During the studies, the care and use of animals were conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC)

Novel approach to characterize signal transduction patways in pancreatic tumor cell lines

1998 ◽  
Vol 114 ◽  
pp. A465
Author(s):  
R. Günther ◽  
I. Stolze ◽  
M. Witt ◽  
U.R. Fölsch ◽  
W.E. Schmidt
Keyword(s):  
Signal Transduction ◽  
Tumor Cell ◽  
Cell Lines ◽  
Pancreatic Tumor ◽  
Tumor Cell Lines ◽  
Pancreatic Tumor Cell ◽  
Novel Approach

Methylthiouracil-Templated Formation of the Fluorescent Silver Nanocluster and its Application to Bioimaging

2014 ◽  
Vol 937 ◽  
pp. 256-259
Author(s):  
Xiao Qing Xu
Keyword(s):  
Tumor Cell ◽  
Mtt Assay ◽  
Hela Cells ◽  
Cell Imaging ◽  
Silver Nanoclusters ◽  
Cell Toxicity ◽  
Silver Nanocluster ◽  
Novel Approach ◽  
Diphenyltetrazolium Bromide ◽  
Ag Nanoclusters

Herein, we report a novel approach to Methylthiouracil-templated formation of fluorescent Ag nanoclusters and its application to bioimaging. We used fluorescence assay and TEM to characterize the silver nanocluster. The complex can be directly employed into bioimaging HeLa cells. The cell toxicity (3-[4,5-dimethylthiazolyl-2]-2,5-diphenyltetrazolium bromide, MTT) assay demonstrated that the silver nanocluster has only little affect on the cytotoxicity to the cells, which further proves the applicability of the method in tumor cell imaging. This work successfully develops the capping Methylthiouracil scaffolds of silver nanoclusters.

Identification of Novel Small-Molecule Inhibitors for Human Transketolase by High-Throughput Screening with Fluorescent Intensity (FLINT) Assay

2004 ◽  
Vol 9 (5) ◽  
pp. 427-433 ◽  
Author(s):  
Mark X. Du ◽  
Janet Sim ◽  
Lijuan Fang ◽  
Zheng Yin ◽  
Sean Koh ◽  
...  
Keyword(s):  
Tumor Cell ◽  
High Throughput ◽  
High Throughput Screening ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
Metabolic Enzyme ◽  
Fluorescent Intensity ◽  
Novel Approach ◽  
Starting Point

The metabolic enzyme transketolase (TK) plays a crucial role in tumor cell nucleic acid synthesis, using glucose through the elevated nonoxidative pentose phosphate pathway (PPP). Identification of inhibitors specifically targeting TK and preventing the nonoxidative PPP from generating the RNA ribose precursor, ribose-5-phosphate, provides a novel approach for developing effective anticancer therapeutic agents. The full-length human transketolase gene was cloned and expressed in Escherichia coli and the recombinant human transketolase protein purified to homogeneity. A fluorescent intensity (FLINT) assay was developed and optimized. Library compounds were screened in a high-throughput screening (HTS) campaign using the FLINT assay. Fifty-four initial hits were identified. Among them, 2 scaffolds with high selectivity, ideal physiochemical properties, and low molecular weight were selected for lead optimization studies. These compounds specifically inhibited in vitro TK enzyme activity and suppressed tumor cell proliferation in at least 3 cancer cell lines: SW620, LS174T, and MIA PaCa-2. Identification of these active scaffolds represents a good starting point for development of drugs specifically targeting TK and the nonoxidative PPP for cancer therapy.

scholarly journals A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

2017 ◽  
Vol 13 ◽  
pp. 1564-1571 ◽  
Author(s):  
Benedikt C Melzer ◽  
Franz Bracher
Keyword(s):  
Tumor Cell ◽  
Cell Line ◽  
Carboxylic Acids ◽  
Tumor Cell Line ◽  
Cross Coupling ◽  
Novel Approach

Oxoisoaporphine alkaloids are conveniently prepared via direct ring metalation of alkoxy-substituted isoquinolines at C-1, followed by reaction with iodine. Subsequent Suzuki cross-coupling of the resulting 1-iodoisoquinolines to methyl 2-(isoquinolin-1-yl)benzoates and intramolecular acylation of the corresponding carboxylic acids with Eaton’s reagent afforded five alkaloids of the oxoisoaporphine type. The yield of the cyclization step strongly depends on the electrophilic properties of ring B. An alternative cyclization protocol via directed remote metalation of ester and amide intermediates was investigated thoroughly, but found to be not feasible. Two of the alkaloids showed strong cytotoxicity against the HL-60 tumor cell line.

scholarly journals Mechanisms Conferring Resistance to Pro-Apoptotic Cancer Gene Therapy

2011 ◽  
Vol 4 ◽  
pp. JCD.S4686
Author(s):  
Shona T. Dougherty ◽  
Graeme J. Dougherty
Keyword(s):  
Tumor Cell ◽  
Plasmid Vector ◽  
Death Domain ◽  
Tumor Cell Death ◽  
Surface Receptors ◽  
Novel Approach ◽  
Cell Clones ◽  
Ligand Expression

Recently, we have described a novel approach to the treatment of cancer that employs a series of vectors that encode surface expressed chimeric proteins in which the cytoplasmic death domain of Fas is fused in-frame to the extracellular domain of one of a number of cell surface receptors that recognize and bind various ligands that are differentially expressed within the tumor microenvironment. Although the majority of tumor cells transduced with such vectors are killed in the presence of the corresponding cognate ligand, a small percentage survive and in vivo may go on to repopulate a treated tumor. In order to understand the mechanisms employed by tumors to escape the cytotoxic effects of pro-apoptotic signals triggered via Fas, we isolated a large number of 293 tumor cell clones that survive following transfection with a plasmid vector encoding Flk-1/Fas, a chimeric receptor that induces tumor cell death in the presence of the pro-angiogenic cytokine VEGF. Characterization of Flk-1/Fas-positive clones revealed that while survival can most often be attributed simply to the down-regulation of VEGF ligand expression, in cells that express both receptor and ligand, other proteins involved in the regulation of apoptosis may be targeted. Specifically, a Flk-1/Fas-positive, VEGF-positive clone was identified in which expression of APAF-1 was almost completely abrogated.

scholarly journals Antibody-drug conjugate therapies in multiple myeloma—what’s next on the horizon?

2022 ◽  
pp. 617-626
Author(s):  
Monique Hartley-Brown ◽  
Paul Richardson
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Tumor Cell ◽  
Antibody Drug Conjugate ◽  
Incurable Cancer ◽  
Cell Internalization ◽  
Novel Approach ◽  
Fda Approval ◽  
Antibody Drug

Targeted immunotherapy has arisen over the past decade to the forefront of cancer care. Notably, targeted therapies such as antibody-drug conjugates (ADCs) are becoming more recognized for a novel approach in cancer treatment. The mechanism of action of ADCs incorporates a monoclonal antibody portion directed against the tumor cell antigen and attached to the tumoricidal portion via chemical linkage. The binding of the monoclonal antibody portion allows for tumor cell internalization of the ADC and precise release of the toxic payload within the cancer cell. Multiple myeloma (MM) is an incurable cancer for which belantamab mafodotin was the first-in-class ADC to achieve United States Food and Drug Administration (FDA) approval for treatment of this disease. Clinical trials are currently evaluating other ADCs in the treatment of MM. In this review, a look at the current ADCs being tested in MM clinical trials with a focus on those that are more promising and a potential next-in-line for FDA approval for treatment of MM is discussed.

scholarly journals Evaluation of a novel approach to circulating tumor cell isolation for cancer gene panel analysis in patients with breast cancer

2017 ◽  
Vol 13 (5) ◽  
pp. 3025-3031 ◽  
Author(s):  
Soo Jeong Lee ◽  
Cham Han Lee ◽  
Sung Ho Choi ◽  
Sei Hyun Ahn ◽  
Byung Ho Son ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Circulating Tumor Cell ◽  
Cell Isolation ◽  
Gene Panel ◽  
Panel Analysis ◽  
Cancer Gene ◽  
Novel Approach
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