scholarly journals Heart Slice Culture System Reliably Demonstrates Clinical Drug-Related Cardiotoxicity

2020 ◽  
Author(s):  
Jessica M. Miller ◽  
Moustafa H. Meki ◽  
Qinghui Ou ◽  
Sharon A. George ◽  
Anna Gams ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Culture System ◽  
Drug Efficacy ◽  
Heart Tissue ◽  
Significant Loss ◽  
Limiting Factors ◽  
Slice Culture ◽  
Cancer Drugs ◽  
Anti Cancer ◽  
Culture Models

AbstractThe limited availability of human heart tissue and its complex cell composition are major limiting factors for reliable testing drug efficacy, toxicity and understanding mechanism. Recently, we developed a functional human and pig heart slice biomimetic culture system that fully preserves the viability and functionality of 300 µm heart slices for 6 days. Here, we tested the reliability of this culture system in delineating the mechanisms of known anti-cancer drugs that cause cardiomyopathy. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) associated with different mechanisms leading to cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and transcriptome. Slices incubated with any of these drugs for 48 h showed significant loss in viability, cardiomyocyte structure and functionality. Mechanistically, RNA sequencing demonstrated a significant downregulation of cardiac genes and upregulation of oxidative response in doxorubicin-treated tissues. Trastuzumab treatment caused major downregulation in cardiac muscle contraction-related genes, consistent with its clinically known direct effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes in line with its mechanism of action. Heart slices are not only able to demonstrate the expected toxicity of doxorubicin and trastuzumab similar to hiPS-derived-cardiomyocytes; they are superior in detecting sunitinib cardiotoxicity phenotypes and mechanism in the clinically relevant concentration range, 100 nM – 1 µM. These results indicate that heart slice tissue culture models have the potential to become a reliable platform for testing drug toxicity and mechanism of action.

Stereoselective PT complexes as probes of the mechanism of action of Pt anti-cancer drugs

1995 ◽  
Vol 59 (2-3) ◽  
pp. 200
Author(s):  
T.W. Hambley ◽  
G.W. Allen ◽  
R.R. Fenton ◽  
E.C.H. Ling ◽  
H.M. Er ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Cancer Drugs ◽  
Anti Cancer

scholarly journals Systematic Review of Patient-Derived Xenograft Models for Preclinical Studies of Anti-Cancer Drugs in Solid Tumors

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 418 ◽  
Author(s):  
Yoshikatsu Koga ◽  
Atsushi Ochiai
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Solid Tumors ◽  
Cancer Biology ◽  
Drug Efficacy ◽  
Cancer Drugs ◽  
Personalized Care ◽  
Patient Derived Xenograft ◽  
Anti Cancer ◽  
Pdx Models

Patient-derived xenograft (PDX) models are used as powerful tools for understanding cancer biology in PDX clinical trials and co-clinical trials. In this systematic review, we focus on PDX clinical trials or co-clinical trials for drug development in solid tumors and summarize the utility of PDX models in the development of anti-cancer drugs, as well as the challenges involved in this approach, following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Recently, the assessment of drug efficacy by PDX clinical and co-clinical trials has become an important method. PDX clinical trials can be used for the development of anti-cancer drugs before clinical trials, with their efficacy assessed by the modified response evaluation criteria in solid tumors (mRECIST). A few dozen cases of PDX models have completed enrollment, and the efficacy of the drugs is assessed by 1 × 1 × 1 or 3 × 1 × 1 approaches in the PDX clinical trials. Furthermore, co-clinical trials can be used for personalized care or precision medicine with the evaluation of a new drug or a novel combination. Several PDX models from patients in clinical trials have been used to assess the efficacy of individual drugs or drug combinations in co-clinical trials.

scholarly journals Network-based machine learning in colorectal and bladder organoid models predicts anti-cancer drug efficacy in patients

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
JungHo Kong ◽  
Heetak Lee ◽  
Donghyo Kim ◽  
Seong Kyu Han ◽  
Doyeon Ha ◽  
...  
Keyword(s):  
Machine Learning ◽  
Cancer Patient ◽  
Cancer Patients ◽  
Three Dimensional ◽  
Predictive Biomarkers ◽  
Drug Efficacy ◽  
Cancer Drug ◽  
Drug Responses ◽  
Anti Cancer ◽  
Culture Models

Abstract Cancer patient classification using predictive biomarkers for anti-cancer drug responses is essential for improving therapeutic outcomes. However, current machine-learning-based predictions of drug response often fail to identify robust translational biomarkers from preclinical models. Here, we present a machine-learning framework to identify robust drug biomarkers by taking advantage of network-based analyses using pharmacogenomic data derived from three-dimensional organoid culture models. The biomarkers identified by our approach accurately predict the drug responses of 114 colorectal cancer patients treated with 5-fluorouracil and 77 bladder cancer patients treated with cisplatin. We further confirm our biomarkers using external transcriptomic datasets of drug-sensitive and -resistant isogenic cancer cell lines. Finally, concordance analysis between the transcriptomic biomarkers and independent somatic mutation-based biomarkers further validate our method. This work presents a method to predict cancer patient drug responses using pharmacogenomic data derived from organoid models by combining the application of gene modules and network-based approaches.

Mechanism of Action of Anti-Cancer Drugs

1980 ◽  
pp. 49-78
Author(s):  
Kenneth C. Calman ◽  
John F. Smyth ◽  
Martin H. N. Tattersall
Keyword(s):  
Mechanism Of Action ◽  
Cancer Drugs ◽  
Anti Cancer

scholarly journals Using Immunocytochemistry and Fluorescence Microscopy Imaging to Explore the Mechanism of Action of Anti-Cancer Drugs on the Cell Cycle

CourseSource ◽  
2020 ◽  
Vol 7 ◽  
Author(s):  
Allison R. D'Costa ◽  
David W. Barnes ◽  
Alessandra Barrera ◽  
Jennifer Hurst-Kennedy ◽  
Latanya Hammonds-Odie
Keyword(s):  
Cell Cycle ◽  
Fluorescence Microscopy ◽  
Mechanism Of Action ◽  
Cancer Drugs ◽  
Microscopy Imaging ◽  
Anti Cancer

scholarly journals Analysis of Sensitivity and Cell Death Pathways Mediated by Anti-cancer Drugs Using Three-dimensional Culture System

2017 ◽  
Vol 14 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Takeshi Kinoshita ◽  
Hajime Higuchi ◽  
Ayano- Kabashima- ◽  
Gen Sakai ◽  
Yasuo Hamamoto ◽  
...  
Keyword(s):  
Cell Death ◽  
Culture System ◽  
Three Dimensional ◽  
Cancer Drugs ◽  
Cell Death Pathways ◽  
Anti Cancer ◽  
Three Dimensional Culture

scholarly journals Stem-like Cancer Cells in a Dynamic 3D Culture System: A Model to Study Metastatic Cell Adhesion and Anti-cancer Drugs

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1434 ◽  
Author(s):  
Paolillo ◽  
Colombo ◽  
Serra ◽  
Belvisi ◽  
Papetti ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cancer Cells ◽  
Culture System ◽  
Human Fibroblasts ◽  
3D Culture ◽  
Target Tissue ◽  
Cancer Drugs ◽  
Mesenchymal Transition ◽  
Anti Cancer

Metastatic spread is mainly sustained by cancer stem cells (CSC), a subpopulation of cancer cells that displays stemness features. CSC are thought to be derived from cancer cells that undergo epithelial to mesenchymal transition (EMT), thus acquiring resistance to anoikis and anti-cancer drugs. After detachment from the primary tumor mass, CSC reach the blood and lymphatic flow, and disseminate to the target tissue. This process is by nature dynamic and in vitro models are quite far from the in vivo situation. In this study, we have tried to reproduce the adhesion process of CSC to a target tissue by using a 3D dynamic cell culture system. We isolated two populations of 3D tumor spheroids displaying CSC-like features from breast carcinoma (MCF-7) and lung carcinoma (A549) cell lines. Human fibroblasts were layered on a polystyrene scaffold placed in a dynamically perfused millifluidic system and then the adhesion of tumor cell derived from spheroids to fibroblasts was investigated under continuous perfusion. After 24 h of perfusion, we found that spheroid cells tightly adhered to fibroblasts layered on the scaffold, as assessed by a scanning electron microscope (SEM). To further investigate mechanisms involved in spheroid cell adhesion to fibroblasts, we tested the effect of three RGD integrin antagonists with different molecular structures on cell adhesion; when injected into the circuit, only cilengitide was able to inhibit cell adhesion to fibroblasts. Although our model needs further refinements and improvements, we do believe this study could represent a promising approach in improving current models to study metastatic infiltration in vitro and a new tool to screen new potential anti-metastatic molecules.

Novel mononuclear ruthenium(ii) complexes as potent and low-toxicity antitumour agents: synthesis, characterization, biological evaluation and mechanism of action

RSC Advances ◽  
2016 ◽  
Vol 6 (36) ◽  
pp. 29963-29976 ◽  
Author(s):  
Pengchao Hu ◽  
Ying Wang ◽  
Yan Zhang ◽  
Hui Song ◽  
Fangfang Gao ◽  
...  
Keyword(s):  
Side Effects ◽  
Mechanism Of Action ◽  
Biological Evaluation ◽  
Cancer Drugs ◽  
Antitumour Agents ◽  
Anti Cancer ◽  
Antitumour Agent ◽  
Low Toxicity

The ruthenium(ii) complex, [Ru(dmb)2(salH)]PF6(Ru-2), is considered a potential antitumour agent that could avoid the side-effects of platinum-based anti-cancer drugs, such as cisplatin, carboplatin or oxaliplatin.

Effects of sterilization modes on the mechanical strengths of plaster of paris implants

1989 ◽  
Vol 47 ◽  
pp. 890-891
Author(s):  
K. Cowden ◽  
B. Giammara ◽  
T. Devine ◽  
J. Hanker
Keyword(s):  
Gamma Radiation ◽  
Calcium Sulfate ◽  
Significant Loss ◽  
Potassium Sulfate ◽  
Limiting Factors ◽  
Radiation Sterilization ◽  
Plaster Of Paris ◽  
Hardness Tester ◽  
Dry Heat ◽  
Calcium Sulfate Hemihydrate

Plaster of Paris (calcium sulfate hemihydrate, CaSO4. ½ H2O) has been used as a biomedical implant material since 1892. One of the primary limiting factors of these implants is their mechanical properties. These materials have low compressive and tensile strengths when compared to normal bone. These are important limiting factors where large biomechanical forces exist. Previous work has suggested that sterilization techniques could affect the implant’s strength. A study of plaster of Paris implant mechanical and physical properties to find optimum sterilization techniques therefore, could lead to a significant increase in their application and promise for future use as hard tissue prosthetic materials.USG Medical Grade Calcium Sulfate Hemihydrate Types A, A-1 and B, were sterilized by dry heat and by gamma radiation. Types A and B were additionally sterilized with and without the setting agent potassium sulfate (K2SO4). The plaster mixtures were then moistened with a minimum amount of water and formed into disks (.339 in. diameter x .053 in. deep) in polyethylene molds with a microspatula. After drying, the disks were fractured with a Stokes Hardness Tester. The compressive strengths of the disks were obtained directly from the hardness tester. Values for the maximum tensile strengths σo were then calculated: where (P = applied compression, D = disk diameter, and t = disk thickness). Plaster disks (types A and B) that contained no setting agent showed a significant loss in strength with either dry heat or gamma radiation sterilization. Those that contained potassium sulfate (K2SO4) did not show a significant loss in strength with either sterilization technique. In all comparisons (with and without K2SO4 and with either dry heat or gamma radiation sterilization) the type B plaster had higher compressive and tensile strengths than that of the type A plaster. The type A-1 plaster however, which is specially modified for accelerated setting, was comparable to that of type B with K2SO4 in both compressive and tensile strength (Table 1).

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