scholarly journals Long-term non-invasive drug treatments for adult zebrafish

2021 ◽  
Author(s):  
Yuting Lu ◽  
E. Elizabeth Patton
Keyword(s):  
Drug Resistance ◽  
Drug Efficacy ◽  
Drug Formulation ◽  
Tumour Regression ◽  
Adult Zebrafish ◽  
Zebrafish Model ◽  
Invasive Approach ◽  
Acquired Drug Resistance ◽  
Non Invasive

Zebrafish embryos are widely used for drug-discovery however administering drugs to adult zebrafish is limited by current protocols that can cause stress. Here, we develop a drug formulation and administration method for adult zebrafish by producing food-based drug pellets which are consumed voluntarily. We apply this to zebrafish with BRAF-mutant melanoma, a model that has significantly advanced our understanding of melanoma progression, but not of drug resistance due to the limitations of current treatment methods. Short-term, precise, and daily dosing with drug-pellets made with the BRAFV600E inhibitor, vemurafenib, led to tumour regression. On-target drug efficacy was determined by phospho-ERK staining. Continued drug treatment led to the emergence, for the first time in zebrafish, of acquired drug resistance and melanoma relapse, modelling the responses seen in melanoma patients. This method presents a controlled, non-invasive approach that permits long-term drug studies, and can be widely applied to any adult zebrafish model.

Amelogenesis Imperfecta: A Non-Invasive Approach to Improve Esthetics in Young Patients. Report of Two Cases

2017 ◽  
Vol 41 (5) ◽  
pp. 332-335
Author(s):  
Maria Grazia Cagetti ◽  
Stefano Cattaneo ◽  
Ye Qing Hu ◽  
Guglielmo Campus
Keyword(s):  
Young Patients ◽  
Minimal Invasive ◽  
Amelogenesis Imperfecta ◽  
Invasive Treatment ◽  
Invasive Approach ◽  
Resin Infiltration ◽  
Non Invasive ◽  
Minimal Invasive Treatment ◽  
Infiltrant Resin

Objective–Evaluate esthetic and functional efficacy of infiltrant resin (Icon, DMG, Hamburg, Germany) in Amelogenesis Imperfecta's treatment. Study design: Two adolescent patients, G.S. (13 years old) and C.M. (15 years old), affected by the hypomaturation type of Amelogenesis Imperfecta, were treated with Icon resin and were followed for twelve months. Results: Treated teeth show an excellent aesthetical result immediately after the resin application, effect that lasts in the long-term (six and twelve months follow-up examinations); the dental wear's progression seems to be clinically arrested. Conclusions: Resin infiltration has proven to be a minimal invasive treatment for dental discoloration, less aggressive than conventional procedures. This approach might be recommended for a stable esthetical improvement in moderate AI's lesions especially in children and adolescents.

RNAi-mediated functional analysis of pathways influencing cancer cell drug resistance

2009 ◽  
Vol 11 ◽  
Author(s):  
Alvin J.X. Lee ◽  
Richard Kolesnick ◽  
Charles Swanton
Keyword(s):  
Drug Resistance ◽  
High Throughput Screening ◽  
Drug Sensitivity ◽  
Drug Efficacy ◽  
Successive Treatment ◽  
Acquired Drug Resistance ◽  
Treatment Regimens ◽  
Rnai Technology

Acquired drug resistance limits the efficacy of cytotoxics used in the management of haematological and solid tumours and is responsible for the declining clinical benefit following successive treatment regimens in metastatic cancers. Treatment failure has a major impact on quality of life and survival in advanced disease. Defining pathways of intrinsic and acquired drug resistance may provide new targets to prolong drug efficacy and time to disease progression. Predicting the intrinsic drug sensitivity of human tumours in advance of cytotoxic therapy is of paramount importance in order to limit unnecessary toxicity and optimise treatment outcome. RNA interference (RNAi) provides a powerful tool to annotate gene function and systematically define drug-resistance pathways. High-throughput screening RNAi technology has provided evidence for drug-specific resistance pathways as well as novel pathways implicated in multidrug sensitivity. The challenge is how to integrate these data with biological samples to define relevant drug-resistant pathways in vivo.

scholarly journals The Long-Term DEHP Exposure Confers Multidrug Resistance of Triple-Negative Breast Cancer Cells through ABC Transporters and Intracellular ROS

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 949
Author(s):  
Mahendra Jadhao ◽  
Eing-Mei Tsai ◽  
Ho-Chun Yang ◽  
Yih-Fung Chen ◽  
Shih-Shin Liang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Abc Transporters ◽  
Breast Cancer Cells ◽  
Acquired Drug Resistance ◽  
Intracellular Ros ◽  
Dehp Exposure

The characteristics of phthalates had been thought to be similar to endocrine disruptors, which increases cancer risk. The role of phthalates in acquired drug resistance remains unclear. In this study, we investigated the effect of di-(2-ethylhexyl) phthalate (DEHP) on acquired drug resistance in breast cancer. MCF7 and MDA-MB-231 breast cancer cells were exposed to long-term physiological concentration of DEHP for more than three months. Long-exposure DEHP permanently attenuated the anti-proliferative effect of doxorubicin with estrogen receptor-independent activity even after withdrawal of DEHP. Long term DEHP exposure significantly reduced ROS (O2−) level in MDA-MB-231 cells while increased in MCF7 cells. ATP-binding cassette (ABC) transporters possess a widely recognized mechanism of drug resistance and are considered a target for drug therapy. Upregulation of ABC family proteins, ABCB-1 and ABCC-1 observed in DEHP-exposed clones compared to doxorubicin-resistant (DoxR) and parental MDA-MB-231 cells. A viability assay showed enhanced multidrug resistance in DEHP-exposed clones against Dox, topotecan, and irinotecan. Inhibition of ABC transporters with tariquidar, enhanced drug cytotoxicity through increased drug accumulation reversing acquired multidrug resistance in MDA-MB-231 breast cancer cells. Tariquidar enhanced Dox cytotoxicity by increasing intracellular ROS production leading to caspase-3 mediated apoptosis. Activation of PI3K/Akt signaling enhanced proliferation and growth of DEHP-exposed MDA-MB-231 cells. Overall, long-term DEHP exposure resulted in acquired multidrug resistance by upregulating ABCB-1 and ABCC1; apart from proliferation PI3K/Akt may be responsible for acquired drug resistance through ABC transporter upregulation. Targeting ABCB1 and ABCC1 with tariquidar may be a promising strategy for reversing the acquired multidrug resistance of triple-negative breast cancer cells.

Abstract P212: Haploinsufficiency of Target of Rapamycin Attenuates Different Forms of Cardiomyopathies in Adult Zebrafish

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Xiaojing Sun ◽  
Yonghe Ding ◽  
Wei Huang ◽  
Tiffany Hoage ◽  
Margaret Redfield ◽  
...  
Keyword(s):  
Target Of Rapamycin ◽  
Adult Zebrafish ◽  
Long Term Effects ◽  
Tor Signaling ◽  
Zebrafish Model ◽  
Genetic Studies ◽  
Vertebrate Model ◽  
Cardioprotective Effects ◽  
Cardiac Enlargement

In contrast to the wide application of zebrafish embryos in developmental genetic studies, the value of an adult zebrafish to dissect signaling pathways in human diseases such as cardiomyopathy remains largely elusive. Previously, we have established anemic tr265/tr265 fish as the first adult zebrafish model of cardiomyopathy. Here, we generate the second adult zebrafish cardiomyopathy model induced by injection of a single bolus of doxorubicin (DOX). Despite their different pathogenesis, cardiac enlargement induced by either anemia or DOX can be effectively attenuated by inhibition of target of rapamycin (TOR) signaling via rapamycin treatment. However, along the progression of both models, we have also detected dynamic TOR activity and distinct effects of TOR signaling inhibition at different stages of pathogenesis. To assess the long term effects of TOR haploinsufficiency, we utilized a zebrafish target of rapamycin (ztor) mutant that was identified from a mutagenesis screen. We show that sustained TOR inhibition in ztor/+ improved cardiac function, prevented pathological remodeling events, and ultimately reduced mortality in both adult fish models of cardiomyopathy. Mechanistically, these cardioprotective effects are conveyed by the anti-hypertrophy, anti-apoptosis, and pro-autophagy function of TOR signaling inhibition. Together, our results prove adult zebrafish as a novel vertebrate model for human cardiomyopathies and provide genetic evidences for a cardioprotective function of TOR signaling inhibition in different forms of cardiomyopathies.

scholarly journals Long-term activation of SAPK/JNK, p38 kinase and fas-L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance

2004 ◽  
Vol 112 (6) ◽  
pp. 974-985 ◽  
Author(s):  
Anamaria Brozovic ◽  
Gerhard Fritz ◽  
Markus Christmann ◽  
Jochen Zisowsky ◽  
Ulrich Jaehde ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Carcinoma Cells ◽  
P38 Kinase ◽  
Human Carcinoma ◽  
Acquired Drug Resistance ◽  
Fas L

scholarly journals Angiogenesis and chemotherapy resistance: optimizing chemotherapy scheduling using mathematical modeling

2021 ◽  
Author(s):  
Mariusz Bodzioch ◽  
Piotr Bajger ◽  
Urszula Foryś
Keyword(s):  
Mathematical Modeling ◽  
Drug Resistance ◽  
Chemotherapy Resistance ◽  
Maximum Tolerated Dose ◽  
Attractive Alternative ◽  
Acquired Drug Resistance ◽  
Control Techniques ◽  
Drug Doses ◽  
Metronomic Therapy

AbstractChemotherapy remains a widely used cancer treatment. Acquired drug resistance may greatly reduce the efficacy of treatment and means to overcome it are a topic of active discussion among researchers. One of the proposed solutions is to shift the therapeutic paradigm from complete eradication of cancer to maintenance, i.e., to treat it as a chronic disease. A concept of metronomic therapy (low chemotherapy doses applied continuously) emerged in early 2000s and was henceforth shown to offer a number of benefits, including targeting endothelial cells and reducing acquired drug resistance. Using mathematical modeling and optimal control techniques, we investigate the hypothesis that lower doses of chemotherapy are beneficial for patients. Our analysis of a mathematical model of tumor growth under angiogenic signaling proposed by Hahnfeldt et al. adapted to heterogeneous tumors treated by combined anti-angiogenic agent and chemotherapy offers insights into the effects of metronomic therapy. Firstly, assuming constant long-term drug delivery, the model suggests that the longest survival time is achieved for intermediate drug doses. Secondly, by formalizing the notion of the therapeutic target being maintenance rather than eradication, we show that in the short term, optimal chemotherapy scheduling consists mainly of a drug applied at a low dose. In conclusion, we suggest that metronomic therapy is an attractive alternative to maximum tolerated dose therapies to be investigated in experimental settings and clinical trials.

scholarly journals A chemical-genetic map of the pathways controlling drug potency in Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Shuqi Li ◽  
Nicholas C Poulton ◽  
Jesseon S Chang ◽  
Zachary A Azadian ◽  
Michael A Dejusus ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Genetic Map ◽  
Drug Efficacy ◽  
Multidrug Resistant ◽  
Loss Of Function ◽  
Intrinsic Resistance ◽  
Acquired Drug Resistance ◽  
Chemical Genetic ◽  
Resistant Tuberculosis

Mycobacterium tuberculosis infection is notoriously difficult to treat. To define the bacterial determinants that limit treatment efficacy, we developed a CRISPRi chemical genetics platform to titrate the expression of nearly all Mtb genes and quantify bacterial fitness in the presence of different drugs. Mining this dataset, we discovered diverse mechanisms of intrinsic drug resistance, unveiling hundreds of potential targets for synergistic drug combinations. Combining our data with comparative genomics of Mtb clinical isolates, we further identified new mechanisms of acquired drug resistance, one of which is associated with the emergence of a multidrug-resistant tuberculosis (TB) outbreak in South America. Lastly, we make the unexpected discovery of loss-of-function mutations in the intrinsic resistance factor whiB7 in an entire Mtb sublineage endemic to Southeast Asia, presenting an opportunity to repurpose macrolides to treat TB. This chemical-genetic map provides a rich resource to understand drug efficacy and guide future TB drug development and treatment.

scholarly journals The Inhibition of CDK8/19 Mediator Kinases Prevents the Development of Resistance to EGFR-Targeting Drugs

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 144
Author(s):  
Amanda C. Sharko ◽  
Chang-Uk Lim ◽  
Martina S. J. McDermott ◽  
Chuck Hennes ◽  
Kingsavanh P. Philavong ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Growth Factor Receptor ◽  
Tumor Resistance ◽  
Acquired Drug Resistance ◽  
Transcriptional Reprogramming ◽  
Development Of Resistance ◽  
Transcriptional Changes ◽  
Epidermal Growth

Drug resistance is the main obstacle to achieving cures with both conventional and targeted anticancer drugs. The emergence of acquired drug resistance is initially mediated by non-genetic transcriptional changes, which occur at a much higher frequency than mutations and may involve population-scale transcriptomic adaptation. CDK8/19 kinases, through association with transcriptional Mediator complex, regulate transcriptional reprogramming by co-operating with different signal-responsive transcription factors. Here we tested if CDK8/19 inhibition could prevent adaptation to drugs acting on epidermal growth factor receptor (EGFR/ERBB1/HER1). The development of resistance was analyzed following long-term exposure of BT474 and SKBR3 breast cancer cells to EGFR-targeting small molecules (gefitinib, erlotinib) and of SW48 colon cancer cells to an anti-EGFR monoclonal antibody cetuximab. In all cases, treatment of small cell populations (~105 cells) with a single dose of the drug initially led to growth inhibition that was followed by the resumption of proliferation and development of drug resistance in the adapted populations. However, this adaptation was always prevented by the addition of selective CDK8/19 inhibitors, even though such inhibitors alone had only moderate or no effect on cell growth. These results indicate that combining EGFR-targeting drugs with CDK8/19 inhibitors may delay or prevent the development of tumor resistance to therapy.

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