Book ChapterDOI
Mechanisms of multidrug resistance in cancer.
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TLDR
Identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing clinical samples could help to predict theDevelopment of resistance and lead to treatments designed to circumvent it.Abstract:
The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anticancer drug and can develop by numerous mechanisms including decreased drug uptake, increased drug efflux, activation of detoxifying systems, activation of DNA repair mechanisms, evasion of drug-induced apoptosis, etc. In the first part of this chapter, we briefly summarize the current knowledge on individual cellular mechanisms responsible for MDR, with a special emphasis on ATP-binding cassette transporters, perhaps the main theme of this textbook. Although extensive work has been done to characterize MDR mechanisms in vitro, the translation of this knowledge to the clinic has not been crowned with success. Therefore, identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing clinical samples could help to predict the development of resistance and lead to treatments designed to circumvent it. Our thoughts about translational research needed to achieve significant progress in the understanding of this complex phenomenon are therefore discussed in a third section. The pleotropic response of cancer cells to chemotherapy is summarized in a concluding diagram.read more
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Journal ArticleDOI
Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Daniel Martinez Molina,Rozbeh Jafari,Marina Ignatushchenko,Takahiro Seki,E. Andreas Larsson,Chen Dan,Lekshmy Sreekumar,Yihai Cao,Yihai Cao,Pär Nordlund,Pär Nordlund +10 more
TL;DR: This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins and validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues.
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Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes
TL;DR: Decreased accumulation is one of the most common features resulting in cisplatin resistance, and seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisPlatin, and decreased fluid phase endocytosis.
Journal ArticleDOI
Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade.
Zhaolin Chen,Tianlu Shi,Lei Zhang,Pengli Zhu,Mingying Deng,Cheng Huang,Tingting Hu,Ling Jiang,Jun Li +8 more
TL;DR: Recent findings suggest that efflux pumps of the ABC transporter family are subject to epigenetic gene regulation, and this review summarizes recent findings of the role of ABC efflux transporters in MDR.
Journal ArticleDOI
The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade.
TL;DR: The development of new compounds and the re-evaluation of compounds originally designed for other targets as transport inhibitors of ATP-dependent drug efflux pumps are summarized.
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The Clinical Relevance of Cancer Cell Lines
TL;DR: This work reviews the major events in the development of the in vitro models and the emergence of new technologies that have revealed important issues and limitations concerning human cancer cell lines as models and develops new in vitro preclinical models that would substantially increase the success rate ofnew in vitro-assessed cancer treatments.
References
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Journal ArticleDOI
Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters
Mitsunori Okabe,Gergely Szakács,Gergely Szakács,Mark Reimers,Mark Reimers,Toshihiro Suzuki,Toshihiro Suzuki,Matthew D. Hall,Takaaki Abe,John N. Weinstein,Michael M. Gottesman +10 more
TL;DR: The results indicate that the gene expression database can be used to identify SLCO and SLC22 family members that confer sensitivity to cancer cells.
Journal ArticleDOI
Variants in the SLCO1B3 gene : Interethnic distribution and association with paclitaxel pharmacokinetics
Nicola F. Smith,Steven Marsh,TJ Scott-Horton,Akinobu Hamada,Stephan Mielke,Klaus Mross,William D. Figg,Jaap Verweij,Howard L. McLeod,Alex Sparreboom +9 more
TL;DR: The studied SNPs in SLCO1B3 appear to play a limited role in the disposition of paclitaxel, although their clinical significance in other ethnic populations remains to be investigated.
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Molecular Concepts Analysis Links Tumors, Pathways, Mechanisms, and Drugs
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TL;DR: The utility of the approach is demonstrated by highlighting molecular concepts analyses of Myc pathway activation, breast cancer relapse, and retinoic acid treatment by developing an analysis platform, the Molecular Concepts Map.
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Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein
TL;DR: Transfectants of Spgp transfectants have a low level resistance to Taxol but not to other drugs that form part of the multidrug resistance phenotype, suggesting a conservation in some functions of Pgps across large evolutionary distance.
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Clinical significance of P-glycoprotein expression and function for response to induction chemotherapy, relapse rate and overall survival in acute leukemia.
Christian Wuchter,K Leonid,V. Ruppert,Martin Schrappe,Thomas Büchner,Claudia Schoch,T Haferlach,Jochen Harbott,Richard Ratei,Bernd Dörken,Wolf-Dieter Ludwig +10 more
TL;DR: The data demonstrate a prognostic impact of P-gp in AML but not ALL and indicate that the functional rh123-efflux assay should be preferred for flow-cytometric P-GP evaluation in acute leukemia compared with P- gp expression analysis by monoclonal antibodies.