scholarly journals LS‐106, a novel EGFR inhibitor targeting C797S, exhibits anti‐tumor activities both in vitro and in vivo

2021 ◽  
Author(s):  
Yingqiang Liu ◽  
Mengzhen Lai ◽  
Shan Li ◽  
Yanan Wang ◽  
Fang Feng ◽  
...  
Keyword(s):  
Egfr Inhibitor

EGFR Inhibitor Gefitinib Induces Cardiotoxicity through the Modulation of Cardiac PTEN/Akt/FoxO3a Pathway and Reactive Metabolites Formation: In Vivo and in Vitro Rat Studies

2020 ◽  
Vol 33 (7) ◽  
pp. 1719-1728 ◽  
Author(s):  
Ali Alhoshani ◽  
Fawaz E. Alanazi ◽  
Moureq R. Alotaibi ◽  
Mohamed W. Attwa ◽  
Adnan A. Kadi ◽  
...  
Keyword(s):  
Reactive Metabolites ◽  
Egfr Inhibitor

scholarly journals YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFRL858R, T790M -mutant resistance in vitro and in vivo

2018 ◽  
Vol 7 (4) ◽  
pp. 1430-1439
Author(s):  
Zhang Zhang ◽  
Jian Zou ◽  
Lei Yu ◽  
Jinfeng Luo ◽  
Yan Li ◽  
...  
Keyword(s):  
Egfr Inhibitor

The EGFR-Inhibitor Erlotinib Induces Differentiation, Cell Cycle Arrest and Apoptosis in EGFR-Negative Cells of MDS and AML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 399-399
Author(s):  
Simone Boehrer ◽  
Lionel Ades ◽  
Thorsten Braun ◽  
Lorenzo Galluzzi ◽  
Jennifer Grosjean ◽  
...  
Keyword(s):  
Cell Cycle ◽  
High Risk ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Normal Karyotype ◽  
Egfr Inhibitor ◽  
Knock Down ◽  
Differentiation Block

Abstract Background: The EGFR-inhibitor erlotinib was designed to antagonize the deregulated EGFR-activity in solid tumors. After showing that the EGFR-inhibitor erlotinib induces apoptosis in EGFR-negative ex vivo cells of patients with MDS and AML while sparing normal CD34-positive progenitor cells (ASH 2006, abst n°856), we here update these results and identify crucial molecules conveying this off-target effect. Methods: Ex vivo cells from patients with MDS and AML and myeloid cell lines (P39, KG-1, HL-60) were incubated with 10μM erlotinib, and their potential to differentiate (CD11b and Giemsa staining), to arrest the cell cycle (PI-staining), and to undergo apoptosis (AnnexinV/PI-staining) were tested. Mechanisms of action of erlotinib were studied by immunoflourescence, immunoblotting and siRNAs. To verify the anti-neoplastic effect in vivo, SCID mice were inoculated intraperitoneally with KG-1 cells and erlotinib administered(100mg/kg/day orally,5 days/week, starting on day 7). Results: Erlotinib overcame the leukemia-associated differentiation block in P39, HL-60 and CD34-positive patient cells as demonstrated by an increased surface expression of CD11b and the induction of morphological differentiation. This effect depended on PDGFRb- and Src-mediated signalling, as shown by the inhibition of erlotinib-induced differentiation upon siRNA knock-down of these molecules. Noteworthy, erlotinib was able to overcome the differentiation block in malignant myeloblasts, which are resistant towards its apoptosis-inducing capacity. Furthermore, erlotinib arrested malignant myeloblasts in the G1 phase of the cell cycle after as early as 24h of incubation. Concomitantly, G1/S cyclins E and D1, as well as phosphorylation of the retinoblastoma protein (serines 807/811, 780 and 795) were reduced. Determining the pathways underlying erlotinib’s ability to induce apoptosis we found that erlotinib disrupted JAK-STAT signaling as demonstrated by an abrogation of constitutive JAK2 (tyrosine 1007/1008) and STAT5 (tyrosine 694) phosphorylation in KG-1 cells. In apoptosis-sensitive KG-1 cells, abrogation of JAK2 expression by siRNA alone was sufficient to diminish activation of STAT-5 and to concomitantly induce apoptosis. Of note, combination of JAK2 knock-down and erlotinib did not cause more apoptosis than erlotinib alone supporting that erlotinib induces apoptosis at least in part by inhibiting JAK2. Assessing more closely the apoptosis-inducing capacity of erlotinib on CD34+ bone marrow cells from AML and MDS patients demonstrates that apoptosis induction (increase of at least 15%) is more often observed in overt AML (7/10 cases) than in high-risk (3/7 cases) and low-risk MDS (2/7 cases). In addition, AML and high-risk MDS samples with a normal karyotype exhibited a higher erlotinib response ex vivo than those with abnormal karyotype. Finally, in vivo efficacy of erlotinib was observed in the SCID mouse model inoculated intraperitoneally with KG-1 cells, where it significantly decreased leukemia development. Conclusion: we here provide in vitro, ex vivo and in vivo evidence for a potential therapeutic interest of erlotinib in MDS and AML and delineate important mechanisms underlying its off-target effects in EGFR-negative blast cells.

Induction and Differentiation of Dental Epithelium in Vivo and in Vitro

1982 ◽  
Vol 40 ◽  
pp. 142-145
Author(s):  
E. J. Kollar
Keyword(s):  
Connective Tissue ◽  
Oral Mucosa ◽  
Basal Lamina ◽  
Functional Derivatives ◽  
Specific Source ◽  
Dental Epithelium ◽  
Connective Tissue Stroma

The differentiation and maintenance of many specialized epithelial structures are dependent on the underlying connective tissue stroma and on an intact basal lamina. These requirements are especially stringent in the development and maintenance of the skin and oral mucosa. The keratinization patterns of thin or thick cornified layers as well as the appearance of specialized functional derivatives such as hair and teeth can be correlated with the specific source of stroma which supports these differentiated expressions.

Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

1982 ◽  
Vol 40 ◽  
pp. 210-211
Author(s):  
M.J. Murphy ◽  
R.R. Price ◽  
J.C. Sloman
Keyword(s):  
Cultured Cells ◽  
Human Tumor ◽  
Cell Type ◽  
Tumor Mass ◽  
Initial Cell ◽  
Cloning Assay ◽  
Human Tumor Cloning ◽  
The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

Ultrastructure of melanocyte-keratinocyte interactions and pigment transfer in vitro

1978 ◽  
Vol 36 (2) ◽  
pp. 650-651
Author(s):  
Raul I. Garcia ◽  
Evelyn A. Flynn ◽  
George Szabo
Keyword(s):  
Direct Injection ◽  
Skin Pigmentation ◽  
Freeze Fracture ◽  
Pigment Granule ◽  
Time Lapse ◽  
Ultrastructural Level ◽  
Lanthanum Tracer ◽  
A Cell

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

In vitro and in vivo polysaccharides assembly: ultrastructural and cytochemical study of growing plant cell wall components.

1978 ◽  
Vol 36 (2) ◽  
pp. 434-435
Author(s):  
D. Reis ◽  
B. Vian ◽  
J. C. Roland
Keyword(s):  
Cell Wall ◽  
Self Assembly ◽  
Plant Cell Wall ◽  
Higher Plants ◽  
Three Dimensional ◽  
Cytochemical Study ◽  
Wall Components

Wall morphogenesis in higher plants is a problem still open to controversy. Until now the possibility of a transmembrane control and the involvement of microtubules were mostly envisaged. Self-assembly processes have been observed in the case of walls of Chlamydomonas and bacteria. Spontaneous gelling interactions between xanthan and galactomannan from Ceratonia have been analyzed very recently. The present work provides indications that some processes of spontaneous aggregation could occur in higher plants during the formation and expansion of cell wall.Observations were performed on hypocotyl of mung bean (Phaseolus aureus) for which growth characteristics and wall composition have been previously defined.In situ, the walls of actively growing cells (primary walls) show an ordered three-dimensional organization (fig. 1). The wall is typically polylamellate with multifibrillar layers alternately transverse and longitudinal. Between these layers intermediate strata exist in which the orientation of microfibrils progressively rotates. Thus a progressive change in the morphogenetic activity occurs.

Probing the ultrastructure of the mitotic and meiotic spindle in eggs: An expeditious approach based on semi-thin (0.25 μm) serial sections

1983 ◽  
Vol 41 ◽  
pp. 552-555
Author(s):  
Conly L. Rieder ◽  
S. Bowser ◽  
R. Nowogrodzki ◽  
K. Ross ◽  
G. Sluder
Keyword(s):  
Small Sample Size ◽  
Small Sample ◽  
Meiotic Spindle ◽  
Serial Sections ◽  
Mitotic Apparatus ◽  
Thin Sections ◽  
Cell Cycles ◽  
Ultrastructural Studies

Eggs have long been a favorite material for studying the mechanism of karyokinesis in-vivo and in-vitro. They can be obtained in great numbers and, when fertilized, divide synchronously over many cell cycles. However, they are not considered to be a practical system for ultrastructural studies on the mitotic apparatus (MA) for several reasons, the most obvious of which is that sectioning them is a formidable task: over 1000 ultra-thin sections need to be cut from a single 80-100 μm diameter egg and of these sections only a small percentage will contain the area or structure of interest. Thus it is difficult and time consuming to obtain reliable ultrastructural data concerning the MA of eggs; and when it is obtained it is necessarily based on a small sample size.We have recently developed a procedure which will facilitate many studies concerned with the ultrastructure of the MA in eggs. It is based on the availability of biological HVEM's and on the observation that 0.25 μm thick serial sections can be screened at high resolution for content (after mounting on slot grids and staining with uranyl and lead) by phase contrast light microscopy (LM; Figs 1-2).

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