scholarly journals Targeting Toxins toward Tumors

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1292 ◽  
Author(s):  
Henrik Franzyk ◽  
Søren Brøgger Christensen
Keyword(s):  
Prostate Cancer ◽  
Cancer Tissue ◽  
Malignant Cells ◽  
Enzyme Prodrug Therapy ◽  
Benign Tissue ◽  
Minor Part ◽  
A Minor ◽  
Cancer Diseases ◽  
Antibody Drug ◽  
Target Cancer

Many cancer diseases, e.g., prostate cancer and lung cancer, develop very slowly. Common chemotherapeutics like vincristine, vinblastine and taxol target cancer cells in their proliferating states. In slowly developing cancer diseases only a minor part of the malignant cells will be in a proliferative state, and consequently these drugs will exert a concomitant damage on rapidly proliferating benign tissue as well. A number of toxins possess an ability to kill cells in all states independently of whether they are benign or malignant. Such toxins can only be used as chemotherapeutics if they can be targeted selectively against the tumors. Examples of such toxins are mertansine, calicheamicins and thapsigargins, which all kill cells at low micromolar or nanomolar concentrations. Advanced prodrug concepts enabling targeting of these toxins to cancer tissue comprise antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lectin-directed enzyme-activated prodrug therapy (LEAPT), and antibody-drug conjugated therapy (ADC), which will be discussed in the present review. The review also includes recent examples of protease-targeting chimera (PROTAC) for knockdown of receptors essential for development of tumors. In addition, targeting of toxins relying on tumor-overexpressed enzymes with unique substrate specificity will be mentioned.

THE ROLE OF ANTHROPONYMS IN THE SEMANTIC FIELD OF ARTISTIC WORKS

2019 ◽  
Vol 2019 (29) ◽  
pp. 66-77
Author(s):  
Lidiya Derbenyova
Keyword(s):  
Literary Work ◽  
Main Theme ◽  
Semantic Field ◽  
New Meanings ◽  
Minor Part ◽  
The One ◽  
A Minor ◽  
And Storage ◽  
Horizon Of Expectations

The article explores the role of antropoetonyms in the reader’s “horizon of expectation” formation. As a kind of “text in the text”, antropoetonyms are concentrating a large amount of information on a minor part of the text, reflecting the main theme of the work. As a “text” this class of poetonyms performs a number of functions: transmission and storage of information, generation of new meanings, the function of “cultural memory”, which explains the readers’ “horizon of expectations”. In analyzing the context of the literary work we should consider the function of antropoetonyms in vertical context (the link between artistic and other texts, and the groundwork system of culture), as well as in the context of the horizontal one (times’ connection realized in the communication chain from the word to the text; the author’s intention). In this aspect, the role of antropoetonyms in the structure of the literary text is extremely significant because antropoetonyms convey an associative nature, generating a complex mechanism of allusions. It’s an open fact that they always transmit information about the preceding text and suggest a double decoding. On the one hand, the recipient decodes this information, on the other – accepts this as a sort of hidden, “secret” sense.

Electrostatic effects on ionization equilibria: An MNDO study of proton and hydrogen transfer reactions of 4-fluorobutylamine

1990 ◽  
Vol 55 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Zdeněk Friedl ◽  
Stanislav Böhm
Keyword(s):  
Hydrogen Transfer ◽  
Substituent Effects ◽  
Radical Cations ◽  
Transfer Reactions ◽  
Protonated Forms ◽  
Minor Part ◽  
Bond Strengths ◽  
Ionization Equilibria ◽  
A Minor ◽  
Gas Phase Basicities

The relative enthalpies of proton transfer δ ΔH0and homolytic bond strengths δDH0(B-H+) were calculated by the MNDO method for the sp and ap conformers of 4-flurobutylamine. The data obtained, along with the experimental gas phase basicities, are compared with the values predicted by the electrostatic theory. It is shown that the substituent polar effects FD on the basicities of amines are predominantly due to interactions in their protonated forms (X-B-H+) and/or radical-cations (X-B+.), those in the neutral species (X-B) playing a minor part. A contribution, which is considerably more significant in the sp conformer than in the ap conformer, arises probably also from substituent effects on the homolytic bond strength DH0(B-H+.

scholarly journals Poly (ADP-Ribose) Polymerase 1 Protein Expression in Normal Pancreas and Pancreatic Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Roberto Castiglione ◽  
Aldo E. Calogero ◽  
Enzo Vicari ◽  
Giovanna Calabrini ◽  
Anna Cosentino ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Pancreatic Cancer ◽  
Cell Death ◽  
Pancreatic Adenocarcinoma ◽  
Cancer Tissue ◽  
Normal Pancreas ◽  
Normal Prostate ◽  
Cytoplasmic Staining ◽  
Cancer Of The Pancreas ◽  
Parp 1

Pancreatic cancer is a most frequent cancer in Europe, and the majority of cases of cancer of the pancreas are diagnosed above the age of 65. Radical surgery is the first curative treatment of pancreatic cancer, and alternative or combined therapeutic options, in particular, consist of adjuvant or neoadjuvant chemotherapy, with or without radiotherapy. Many factors, including diet and genetics, have been implicated in the development of cancer of the pancreas. Poly (ADP-ribose) polymerase 1 (PARP-1) protein is required for translocation of the apoptosis-inducing factor (AIF) from the mitochondria to the nucleus. It is involved in programmed cell death processes. Different PARP-1 gene expression proteins have been observed in various tumors such as lung, ovarian, endometrial, skin, and glioblastoma. We evaluated the expression of PARP-1 protein in pancreatic adenocarcinoma and normal pancreas tissues by immunohistochemistry. Protein PARP-1 in the nucleus was found in all samples (normal pancreas and pancreatic adenocarcinoma tissues). No cytoplasmic staining was observed in any sample. PARP-1-positive cells resulted higher in the normal pancreas compared with the pancreas with adenocarcinoma. PARP-1 overexpression in prostate cancer tissue compared with normal prostate suggests a greater activity of PARP-1 in these tumors. These findings suggest that PARP-1 expression in prostate cancer is an attempt to trigger apoptosis in this type of tumor, similarl to that reported in other cancers. This finding suggests that PARP-1-mediated cell death pathways are inhibited in this cancer.

scholarly journals Preclinical Characterization of the Distribution, Catabolism, and Elimination of a Polatuzumab Vedotin-Piiq (POLIVY®) Antibody–Drug Conjugate in Sprague Dawley Rats

2021 ◽  
Vol 10 (6) ◽  
pp. 1323
Author(s):  
Victor Yip ◽  
M. Violet Lee ◽  
Ola M. Saad ◽  
Shuguang Ma ◽  
S. Cyrus Khojasteh ◽  
...  
Keyword(s):  
B Cell Lymphoma ◽  
The United States ◽  
Clinical Development ◽  
Sprague Dawley ◽  
Antibody Drug Conjugate ◽  
Post Dose ◽  
Drug Conjugate ◽  
Sprague Dawley Rats ◽  
A Minor ◽  
Antibody Drug

Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma (DLBCL). To support the clinical development of polatuzumab vedotin, we characterized the distribution, catabolism/metabolism, and elimination properties of polatuzumab vedotin and its unconjugated MMAE payload in Sprague Dawley rats. Several radiolabeled probes were developed to track the fate of different components of the ADC, with 125I and 111In used to label the antibody component and 3H to label the MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes into normal or bile-duct cannulated rats, blood, various tissues, and excreta samples were collected over 7–14 days post-dose and analyzed for radioactivity and to characterize the metabolites/catabolites. The plasma radioactivity of polatuzumab vedotin showed a biphasic elimination profile similar to that of unconjugated polatuzumab but different from unconjugated radiolabeled MMAE, which had a fast clearance. The vast majority of the radiolabeled MMAE in plasma remained associated with antibodies, with a minor fraction as free MMAE and MMAE-containing catabolites. Similar to unconjugated mAb, polatuzumab vedotin showed a nonspecific distribution to multiple highly perfused organs, including the lungs, heart, liver, spleen, and kidneys, where the ADC underwent catabolism to release MMAE and other MMAE-containing catabolites. Both polatuzumab vedotin and unconjugated MMAE were mainly eliminated through the biliary fecal route (>90%) and a small fraction (<10%) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with several other minor species. These studies provided significant insight into ADC’s absorption, distribution, metabolism, and elimination (ADME) properties, which supports the clinical development of POLIVY.

scholarly journals Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1727
Author(s):  
Ana Carolina B. Sant’Anna-Silva ◽  
Juan A. Perez-Valencia ◽  
Marco Sciacovelli ◽  
Claude Lalou ◽  
Saharnaz Sarlak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Carbon Metabolism ◽  
Disease Free Survival ◽  
Building Blocks ◽  
Malignant Cells ◽  
Mitochondrial Complex ◽  
Prostate Cancer Cells ◽  
Prostate Cells ◽  
Malignant Prostate

Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the biosynthesis of precursors for building blocks or signaling molecules. In advanced prostate cancer, an upshift of succinate-driven oxidative phosphorylation via mitochondrial Complex II was reported. Here, using untargeted metabolomics, we found succinate accumulation mainly in malignant cells and an anaplerotic effect contributing to biosynthesis, amino acid, and carbon metabolism. Succinate also stimulated oxygen consumption. Malignant prostate cells displayed higher mitochondrial affinity for succinate when compared to non-malignant prostate cells and the succinate-driven accumulation of metabolites induced expression of mitochondrial complex subunits and their activities. Moreover, extracellular succinate stimulated migration, invasion, and colony formation. Several enzymes linked to accumulated metabolites in the malignant cells were found upregulated in tumor tissue datasets, particularly NME1 and SHMT2 mRNA expression. High expression of the two genes was associated with shorter disease-free survival in prostate cancer cohorts. Moreover, in-vitro expression of both genes was enhanced in prostate cancer cells upon succinate stimulation. In conclusion, the data indicate that uptake of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of prostate cancer cells.

scholarly journals Increased expression of ARF GTPases in prostate cancer tissue

SpringerPlus ◽  
2015 ◽  
Vol 4 (1) ◽  
Author(s):  
Claire Morgan ◽  
Paul D Lewis ◽  
Lynda Hopkins ◽  
Stephanie Burnell ◽  
Howard Kynaston ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Tissue ◽  
Prostate Cancer Tissue ◽  
Arf Gtpases

scholarly journals Bioorthogonal Labeling of Human Prostate Cancer Tissue Slice Cultures for Glycoproteomics

2017 ◽  
Vol 56 (31) ◽  
pp. 8992-8997 ◽  
Author(s):  
David R. Spiciarich ◽  
Rosalie Nolley ◽  
Sophia L. Maund ◽  
Sean C. Purcell ◽  
Jason Herschel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tissue Slice ◽  
Human Prostate ◽  
Cancer Tissue ◽  
Human Prostate Cancer ◽  
Bioorthogonal Labeling ◽  
Prostate Cancer Tissue

Formation and dynamics of Saturn and its disk simulated by using a new N-body model

Open Physics ◽  
2003 ◽  
Vol 1 (4) ◽  
Author(s):  
A. Pavlov ◽  
Y. Pavlova
Keyword(s):  
Surface Density ◽  
Electromagnetic Interaction ◽  
The Core ◽  
Body Model ◽  
Magnetic Forces ◽  
Axis Of Rotation ◽  
Gravitational Model ◽  
Minor Part ◽  
Body Self ◽  
A Minor

AbstractThe formation of Saturn and its disk is simulated using a new N-body self-gravitational model. It is demonstrated that the formation of the disk and the planet is the result of gravitational contraction of a slowly rotated particle cloud that have a shape of slightly deformed sphere. The sphere was flattened by a coefficient of 0.8 along the axis of rotation. During the gravitational contraction, the major part of the cloud transformed into a planet and a minor part transformed into a disk. The thin structured disk is a result of the electromagnetic interaction in which the magnetic forces acting on charged particles of the cloud originate in the core of the planet. The simulation program gives such parameters of Saturn as the escape velocity of about 35 km/s at the surface, density, rotational velocities of the rings and temperature distribution.

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