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Oncogene Jan 2023Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate,...
Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate, adriamycin (doxorubicin) and platinum (cisplatin). Due to the rarity of OS, the generation of relevant cell models as tools for drug discovery is paramount to tackling this issue. Four literature databases were systematically searched using pre-determined search terms to identify MAP resistant OS cell lines and patients. Drug exposure strategies used to develop cell models of resistance and the impact of these on the differential expression of resistance associated genes, proteins and non-coding RNAs are reported. A comparison to clinical studies in relation to chemotherapy response, relapse and metastasis was then made. The search retrieved 1891 papers of which 52 were relevant. Commonly, cell lines were derived from Caucasian patients with epithelial or fibroblastic subtypes. The strategy for model development varied with most opting for continuous over pulsed chemotherapy exposure. A diverse resistance level was observed between models (2.2-338 fold) with 63% of models exceeding clinically reported resistance levels which may affect the expression of chemoresistance factors. In vitro p-glycoprotein overexpression is a key resistance mechanism; however, from the available literature to date this does not translate to innate resistance in patients. The selection of models with a lower fold resistance may better reflect the clinical situation. A comparison of standardised strategies in models and variants should be performed to determine their impact on resistance markers. Clinical studies are required to determine the impact of resistance markers identified in vitro in poor responders to MAP treatment, specifically with respect to innate and acquired resistance. A shift from seeking disputed and undruggable mechanisms to clinically relevant resistance mechanisms may identify key resistance markers that can be targeted for patient benefit after a 40-year wait.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Clinical Relevance; Doxorubicin; Neoplasm Recurrence, Local; Osteosarcoma; Drug Resistance, Neoplasm
PubMed: 36434179
DOI: 10.1038/s41388-022-02529-x -
Clinical Therapeutics Nov 2021To best promote drug tolerability and efficacy in the clinic, data from drug-drug interaction (DDI) evaluations and subsequent translation of the results to DDI...
PURPOSE
To best promote drug tolerability and efficacy in the clinic, data from drug-drug interaction (DDI) evaluations and subsequent translation of the results to DDI prevention and/or management strategies must be incorporated into the US Food and Drug Administration (FDA) product labeling in a consistent manner because differences in language might result in varied interpretations. This analysis aimed to assess the consistency in DDI labeling language in New Drug Applications (NDAs).
METHODS
NDAs of recently approved drugs (2012-2020) that increase the exposure of digoxin, midazolam, and S-warfarin, index substrates of P-glycoprotein, cytochrome P450 (CYP) 3A, and CYP2C9 activity, respectively, were fully reviewed. Noninhibitors were also evaluated to appreciate the extent of mechanistic extrapolation in case of negative index studies.
FINDINGS
After a systematic review of the DDI studies available in NDAs, FDA-approved labeling, and commonly used clinical tertiary resources, differences in DDI results presentation and resulting clinical recommendations were found, even for inhibitors that affect similarly the exposure of the same index substrate. Studies with negative results were often reported in the labels without providing mechanistic interpretation, thus limiting the possible extrapolation of this information to other known substrates.
IMPLICATIONS
The variability in language affects how the information was presented to clinicians in tertiary resources. Strategies that aim to improve the translation of mechanistic DDI index studies into consistent labeling recommendations are briefly discussed in this review.
Topics: Digoxin; Drug Interactions; Humans; Language; Midazolam; Pharmaceutical Preparations; Product Labeling; Warfarin
PubMed: 34579970
DOI: 10.1016/j.clinthera.2021.08.016 -
Journal of Drug Targeting Jul 2020Cellular assays are essential in pharmaceutical development of protein-loaded nanomedicine. Cell lines provide robust and efficient models to characterise cytotoxicity,...
Cellular assays are essential in pharmaceutical development of protein-loaded nanomedicine. Cell lines provide robust and efficient models to characterise cytotoxicity, cellular uptake, absorption mechanism, intracellular stability, exocytosis mechanism and therapeutic effects of nanomedicine. GI epithelial cells and goblet cells have been employed to examine protein-loaded nanoparticles . However, the existence of different research protocols hampers the comparison of formulations and obtained results. Although advanced novel microscopy and fluorescent detection techniques are available for facilitating the development of nano-sized formulation, optimised research designs and validated instrument operation procedure are crucial to increase the reliability and validity of research findings. In the current review article, we examined a number of cellular assays, including cellular culture, cytotoxicity assay, cellular uptake assay, transepithelial studies, permeability assays, glucose consumption assays, and exocytosis and endocytosis studies, that have been widely employed for the development of orally administered insulin-loaded nanoparticles. Meanwhile, the role of various technologies, such as CLSM, flow cytometry, ELISA, fluorescence microscopy, microplate reader, and transmission electron microscopy, on visualisation of nanoparticle cellular uptake was evaluated. The following four challenges, including limited nanoparticle diffusion across mucus barrier, unwanted apical exocytosis, P-glycoprotein efflux pumps, endosomal entrapment and lysosomal degradation on protein-loaded nanoparticles, should be addressed in future studies. During formulation optimisation, strategies that can overcome the above hinderance are warranted to maximise oral bioavailability, minimise waste in research funding and facilitate the translation of therapeutic protein-loaded nanomedicine into clinical settings.
Topics: Administration, Oral; Cell Line, Tumor; Humans; Nanoparticles; Proteins
PubMed: 32013626
DOI: 10.1080/1061186X.2020.1726356 -
The Pharmacogenomics Journal Apr 2015The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes... (Meta-Analysis)
Meta-Analysis
The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07-2.01), 2677G>T/A at years 4-5 (OR: 1.37, 95% CI: 1.01-1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03-1.94) and 4-5 (OR: 1.42, 95% CI: 1.05-1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on larger populations and multiethnic groups should help clarify the effect of P-gp polymorphisms upon other outcomes.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adolescent; Adult; Aged; Aged, 80 and over; Anthracyclines; Child; Child, Preschool; Cohort Studies; Cytarabine; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Middle Aged; Observational Studies as Topic; Polymorphism, Genetic; Treatment Outcome; Young Adult
PubMed: 25558979
DOI: 10.1038/tpj.2014.80 -
Endocrinology Aug 2019Anaplastic thyroid cancer (ATC) is an aggressive type of thyroid cancer with a high mortality rate. Cytotoxic drugs are among the treatment modalities usually used for...
Anaplastic thyroid cancer (ATC) is an aggressive type of thyroid cancer with a high mortality rate. Cytotoxic drugs are among the treatment modalities usually used for ATC treatment. However, systemic chemotherapies for ATC have not been shown to have remarkable efficacy. ATP-binding cassette (ABC) transporters have been suggested as a possible mechanism in ATC resistance to chemotherapy. This systematic review was aimed to define the possible roles of ABC transporters in ATC resistance to chemotherapy. Numerous databases, including Scopus, Web of Science, PubMed, Cochrane Library, Ovid, ProQuest, and EBSCO, were searched for papers published since 1990, with predefined keywords. The literature searches were updated twice, in 2015 and 2017. All identified articles were reviewed, and 14 papers that met the inclusion criteria were selected. In the eligible studies, the roles of 10 out of 49 ABC transporters were evaluated; among them, three pumps (ABCB1, ABCC1, and ABCG2) were the most studied transporters in ATC samples. ABCC1 and ABCG2 had the highest expression rates in ATC, and ABCB1 ranked second among the inspected transporters. In conclusion, ABC transporters are the major determinants of ATC resistance to chemotherapy. By identifying these transporters, we can tailor the best treatment approach for patients with ATC. Additional studies are needed to define the exact role of each ABC transporter and other mechanisms in ATC drug resistance.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Animals; Drug Resistance, Neoplasm; Humans; Neoplastic Stem Cells; Signal Transduction; Thyroid Carcinoma, Anaplastic
PubMed: 31271419
DOI: 10.1210/en.2019-00241