Drug Resistance Updates RSS feed: Current Issue. Drug Resistance Updates is a bimonthly publication that contains thought-provoking reviews and commentaries on important developments in drug resistance in infectious disease and cancer. It covers both basic research and clinical aspects of drug resistance, and involves disciplines as diverse as molecular biology, biochemistry, cell biology, pharmacology, microbiology, oncology and clinical medicine. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. • Reviews the best in clinical and basic drug resistance research in oncology and infectious disease • Describes emerging technologies and therapies • Highlights key references in the drug resistance literature • Features commentaries on important research articles • Emphasises common themes in microbial and cancer research Features include: • Clear, concise reviews • Interdisciplinary perspectives • Summary tables and figures to convey key points • Conference reports • Literature analysis If you have a suggestion for a review article title or wish to discuss the opportunity to publish a manuscript of your own in Drug Resistance Updates , please contact the the Publisher: andrew.miller@elsevier.com . http://www.drupjournal.com/?rss=yesElsevier Inc.en © 2012 Published by Elsevier Inc. All rights reserved. Drug Resistance Updates1368-7646151-2February 2012 © 2012 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.drupjournal.com/article/PIIS1368764612000222/abstract?rss=yesEditorial Board10.1016/S1368-7646(12)00022-2Drug Resistance Updates 15, 1 (2012)2012-02-01Drug Resistance Updates2012-02-01151-2S1368-7646(12)X0002-5iihttp://www.drupjournal.com/article/PIIS1368764612000088/abstract?rss=yesDrug Resistance Updates was launched in January 1998. From the very beginning, Dr. Henk Broxterman, an expert in the field of multidrug resistance and tumor angiogenesis and an associate professor at the Vrije Universiteit in Amsterdam, The Netherlands, has served as the Section Editor for anticancer agents. Following the restructuring of the journal in January 2010, Dr. Broxterman became the only Associate Editor of the journal. During his 14 year period with the journal, Dr. Broxterman has built steadily on Drug Resistance Updates’ reputation as a major journal within antineoplastic agents. The great success of the journal including its impressive impact factor of 12.3 (2011 JCR) is to a large extent attributable to the skillful recruiting of invited reviews by Dr. Broxterman over a period of more than a decade. A lot of progresses have been made in anticancer drugs during this period, and Drug Resistance Updates has always been in the frontline in terms of presenting novel therapeutic concepts or emerging drug resistance.EditorialChristian G. Giske, Jos Jonkers10.1016/j.drup.2012.01.007Drug Resistance Updates 15, 1 (2012)2012-02-13Drug Resistance Updates2012-02-13151-2S1368-7646(12)X0002-5Editorial on - The first issue of Drug Resistance Updates11http://www.drupjournal.com/article/PIIS1368764612000131/abstract?rss=yesDrug resistance is a major public health problem that dramatically affects the efficacy of cancer treatment. When resistance to either systemic or targeted drug treatment occurs, tumor cells may become not only resistant to the drug originally administered but also to a wide variety of structurally and mechanistically unrelated drugs. Finding a cure for multidrug-resistant cancer is extremely challenging. Thirty-five years ago, ABCB1 (P-glycoprotein, MDR1), an ATP-dependent drug efflux pump, was found to be expressed in Chinese hamster ovary cells selected for colchicine resistance. Since then, we have learned that multidrug resistance (MDR) develops via numerous additional mechanisms including decreased drug uptake and increased drug efflux (by numerous ABC and non-ABC transporters in addition to ABCB1), activation of detoxifying systems, activation of DNA repair mechanisms, evasion of drug-induced apoptosis, mutated targets, etc.Overcoming multidrug resistance in cancer: 35 years after the discovery of ABCB1Jean-Pierre Gillet, Michael M. Gottesman10.1016/j.drup.2012.03.001Drug Resistance Updates 15, 1 (2012)2012-04-05Drug Resistance Updates2012-04-05151-2S1368-7646(12)X0002-5Editorial on - Multidrug resistance 35 years after ABCB124http://www.drupjournal.com/article/PIIS1368764612000106/abstract?rss=yesAbstract: Members of the solute carrier family of transporters are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. Several of these solute carriers are known to be expressed in cancer cells or cancer cell lines, and decreased cellular uptake of drugs potentially contributes to the development of resistance. As result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. In this review article, we provide an update of this rapidly emerging field, with specific emphasis on the direct contribution of solute carriers to anticancer drug uptake in tumors, the role of these carriers in regulation of anticancer drug disposition, and recent advances in attempts to evaluate these proteins as therapeutic targets.Contribution of tumoral and host solute carriers to clinical drug responseJason A. Sprowl, Torben S. Mikkelsen, Hugh Giovinazzo, Alex Sparreboom10.1016/j.drup.2012.01.009Drug Resistance Updates 15, 1 (2012)2012-03-30Drug Resistance Updates2012-03-30151-2S1368-7646(12)X0002-5Reviews520http://www.drupjournal.com/article/PIIS136876461200009X/abstract?rss=yesAbstract: Resistance of cancer cells to chemotherapeutics and emerging targeted drugs is a devastating problem in the treatment of cancer patients. Multiple mechanisms contribute to drug resistance such as increased drug efflux, altered drug metabolism, secondary mutations in drug targets, and activation of downstream or parallel signal transduction pathways. The rapid kinetics, the reversibility of acquired drug resistance and the absence of genetic mutations suggest an epigenetic basis for drug insensitivity. Similar to the cellular variance seen in the human body, epigenetic mechanisms, through reversible histone modifications and DNA methylation patterns, generate a variety of transcriptional states resulting in a dynamic heterogeneous tumor cell population. Consequently, epigenomes favoring survival in the presence of a drug by aberrant transcription of drug transporters, DNA-repair enzymes and pro-apoptotic factors render cytotoxic and targeted drugs ineffective and allow selection of rare drug-resistant tumor cells. Recent advances in charting cancer genomes indeed strongly indicate a role for epigenetic regulators in driving cancer, which may result in the acquisition of additional (epi)genetic modifications leading to drug resistance. These observations have important clinical consequences as they provide an opportunity for “epigenetic drugs” to change reversible drug-resistance-associated epigenomes to prevent or reverse non-responsiveness to anti-cancer drugs.Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistanceRoel H. Wilting, Jan-Hermen Dannenberg10.1016/j.drup.2012.01.008Drug Resistance Updates 15, 1 (2012)2012-02-22Drug Resistance Updates2012-02-22151-2S1368-7646(12)X0002-5Reviews2138http://www.drupjournal.com/article/PIIS1368764612000076/abstract?rss=yesAbstract: The emergence of clinical drug resistance is still one of the most challenging factors in cancer treatment effectiveness. Until more recently, the assumption has been that random genetic lesions are sufficient to explain the progression of malignancy and escape from chemotherapy. Here we propose an additional perspective, one in which the tumor cells despite the malignant genome could find a microenvironment either within the tumor or as a dormant cell to remain polar and blend into an organized context. Targeting this dynamic interplay could be considered a new avenue to prevent therapeutic resistance, and may even provide a promising effective cancer treatment.The tumor microenvironment is a dominant force in multidrug resistanceAna Luísa Correia, Mina J. Bissell10.1016/j.drup.2012.01.006Drug Resistance Updates 15, 1 (2012)2012-02-15Drug Resistance Updates2012-02-15151-2S1368-7646(12)X0002-5Reviews3949http://www.drupjournal.com/article/PIIS136876461200012X/abstract?rss=yesAbstract: This special issue of Drug Resistance Updates is dedicated to multidrug resistance protein 1 (MDR-1), 35 years after its discovery. While enormous progress has been made and our understanding of drug resistance has become more sophisticated and nuanced, after 35 years the role of MDR-1 in clinical oncology remains a work in progress. Despite clear in vitro evidence that P-glycoprotein (Pgp), encoded by MDR-1, is able to dramatically reduce drug concentrations in cultured cells, and that drug accumulation can be increased by small molecule inhibitors, clinical trials testing this paradigm have mostly failed. Some have argued that it is no longer worthy of study. However, repeated analyses have demonstrated MDR-1 expression in a tumor is a poor prognostic indicator leading some to conclude MDR-1 is a marker of a more aggressive phenotype, rather than a mechanism of drug resistance. In this review we will re-evaluate the MDR-1 story in light of our new understanding of molecular targeted therapy, using breast and lung cancer as examples. In the end we will reconcile the data available and the knowledge gained in support of a thesis that we understand far more than we realize, and that we can use this knowledge to improve future therapies.Targeting MDR in breast and lung cancer: Discriminating its potential importance from the failure of drug resistance reversal studiesLaleh Amiri-Kordestani, Agnes Basseville, Karen Kurdziel, Antonio Tito Fojo, Susan E. Bates10.1016/j.drup.2012.02.002Drug Resistance Updates 15, 1 (2012)2012-04-05Drug Resistance Updates2012-04-05151-2S1368-7646(12)X0002-5Reviews5061http://www.drupjournal.com/article/PIIS1368764612000118/abstract?rss=yesAbstract: Resistance to chemotherapy remains a challenging issue for patients and their physicians. P-glycoprotein (Pgp, MDR1, ABCB1), as well as a family of structurally and functionally related proteins, are plasma membrane transporters able to efflux a variety of substrates from the cell cytoplasm, including chemotherapeutic agents. The discovery of ABCB1 made available a potential target for pharmacologic down-regulation of efflux-mediated chemotherapy resistance. In patients with acute myeloid leukemia (AML), a neoplasm characterized by proliferation of poorly differentiated myeloid progenitor cells, leukemic cells often express ABCB1 at high levels, which may lead to the development of resistance to chemotherapy. Thus, AML seemed to be a likely cancer for which the addition of drug efflux inhibitors to the chemotherapeutic regimen would improve outcomes in patients. Despite this rational hypothesis, the majority of clinical trials evaluating this strategy have failed to reach a positive endpoint, most recently the Eastern Cooperative Oncology Group E3999 trial. Here we review data suggesting the importance of ABCB1 in AML, address the failure of clinical trials to support a therapeutic strategy aimed at modulating ABCB1-mediated resistance, and consider the type of research that should be conducted in this field going forward.Drug resistance: Still a daunting challenge to the successful treatment of AMLBrian C. Shaffer, Jean-Pierre Gillet, Chirayu Patel, Maria R. Baer, Susan E. Bates, Michael M. Gottesman10.1016/j.drup.2012.02.001Drug Resistance Updates 15, 1 (2012)2012-03-14Drug Resistance Updates2012-03-14151-2S1368-7646(12)X0002-5Reviews6269http://www.drupjournal.com/article/PIIS1368764612000064/abstract?rss=yesAbstract: Tyrosine kinases (TKs) are involved in key signaling events/pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Deregulated activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to inhibit specific kinases whose constitutive activity results in specific cancer types. These TKIs have been found to demonstrate effective anticancer activity and some of them have been approved by the Food and Drug Administration for clinical use or are in clinical trials. However, these targeted therapeutic agents are also transported by ATP-binding cassette (ABC) transporters, resulting in altered pharmacokinetics or development of resistance to these drugs in cancer patients. This review covers the recent findings on the interactions of clinically important TKIs with ABC drug transporters. Future research efforts in the development of novel TKIs with specific targets, seeking improved activity, should consider these underlying causes of resistance to TKIs in cancer cells.Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistanceSuneet Shukla, Zhe-Sheng Chen, Suresh V. Ambudkar10.1016/j.drup.2012.01.005Drug Resistance Updates 15, 1 (2012)2012-02-13Drug Resistance Updates2012-02-13151-2S1368-7646(12)X0002-5Reviews7080http://www.drupjournal.com/article/PIIS1368764612000027/abstract?rss=yesAbstract: Drug resistance is one of the most pressing problems in treating cancer patients today. Local and regional disease can usually be adequately treated, but patients eventually die from distant metastases that have become resistant to all available chemotherapy. Although work on cultured tumor cell lines has yielded a lot of information on potential drug resistance mechanisms, it has proven difficult to translate these results to clinical drug resistance in patients. The controversy regarding the contribution of ABC transporters to drug resistance in patients is one example. The study of genetically engineered mouse models (GEMMs), which closely resemble cancer in human patients, can help to bridge this gap. In models for BRCA1- or BRCA2-associated breast cancer, we observed a substantial synergy between the defect in homology-directed DNA repair and sensitivity to DNA-targeting drugs. Nevertheless, tumors are not easily eradicated and eventually drug resistance develops. In this review we will discuss the use of the new generation mouse models to address major clinical problems, such as mechanisms of drug resistance, predicting chemotherapy response or characterizing the nature of residual tumor cells that escape eradication. Moreover, we will address the contribution of ABC transporters to drug resistance in our model.Drug resistance in the mouse cancer clinicSven Rottenberg, Piet Borst10.1016/j.drup.2012.01.001Drug Resistance Updates 15, 1 (2012)2012-02-15Drug Resistance Updates2012-02-15151-2S1368-7646(12)X0002-5Reviews8189http://www.drupjournal.com/article/PIIS1368764612000040/abstract?rss=yesHighlights: ► We review the aspects of MDR that have been mathematically studied. ► We explain how mathematics can be used to study drug resistance. ► We demonstrate how mathematics can be used in combination with experimental and clinical tools.Abstract: Resistance to chemotherapy is a key impediment to successful cancer treatment that has been intensively studied for the last three decades. Several central mechanisms have been identified as contributing to the resistance. In the case of multidrug resistance (MDR), the cell becomes resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered. Mathematical models of drug resistance have dealt with many of the known aspects of this field, such as pharmacologic sanctuary and location/diffusion resistance, intrinsic resistance, induced resistance and acquired resistance. In addition, there are mathematical models that take into account the kinetic/phase resistance, and models that investigate intracellular mechanisms based on specific biological functions (such as ABC transporters, apoptosis and repair mechanisms). This review covers aspects of MDR that have been mathematically studied, and explains how, from a methodological perspective, mathematics can be used to study drug resistance. We discuss quantitative approaches of mathematical analysis, and demonstrate how mathematics can be used in combination with other experimental and clinical tools. We emphasize the potential benefits of integrating analytical and mathematical methods into future clinical and experimental studies of drug resistance.The dynamics of drug resistance: A mathematical perspectiveOrit Lavi, Michael M. Gottesman, Doron Levy10.1016/j.drup.2012.01.003Drug Resistance Updates 15, 1 (2012)2012-03-05Drug Resistance Updates2012-03-05151-2S1368-7646(12)X0002-5Reviews9097http://www.drupjournal.com/article/PIIS1368764612000143/abstract?rss=yesAbstract: While chemotherapy remains the most effective treatment for disseminated tumors, acquired or intrinsic drug resistance accounts for approximately 90% of treatment failure. Multidrug resistance (MDR), the simultaneous resistance to drugs that differ both structurally and mechanistically, often results from drug efflux pumps in the cell membrane that reduce intracellular drug levels to less than therapeutic concentrations. Expression of the MDR transporter P-glycoprotein (P-gp, MDR1, ABCB1) has been shown to correlate with overall poor chemotherapy response and prognosis. This review will focus on collateral sensitivity (CS), the ability of compounds to kill MDR cells selectively over the parental cells from which they were derived. Insights into CS may offer an alternative strategy for the clinical resolution of MDR, as highly selective and potent CS agents may lead to drugs that are effective at MDR cell killing and tumor resensitization. Four main mechanistic hypotheses for CS will be reviewed, followed by a discussion on quantitative and experimental evaluation of CS.Collateral sensitivity as a strategy against cancer multidrug resistanceKristen M. Pluchino, Matthew D. Hall, Andrew S. Goldsborough, Richard Callaghan, Michael M. Gottesman10.1016/j.drup.2012.03.002Drug Resistance Updates 15, 1 (2012)2012-04-09Drug Resistance Updates2012-04-09151-2S1368-7646(12)X0002-5Reviews98105http://www.drupjournal.com/article/PIIS1368764612000155/abstract?rss=yesAbstract: Multidrug resistance (MDR) renders cancer cells relatively invulnerable to treatment with many standard cytotoxic anti-cancer agents. Cancer immunotherapy could be an important adjunct for other strategies to treat MDR positive cancers, as resistance to immunotherapy generally is unrelated to mechanisms of resistance to cytotoxic agents. Immunotherapy to combat MDR positive tumors could use any of the following strategies: direct immune attack against MDR positive cells, using MDR as an immune target to deliver cytotoxic agents, capitalization on other immune properties of MDR positive cells, or conditional immunotoxins expressed under MDR control. Additional insights into the immunogenic potential of some cytotoxic agents can also be brought to bear on these strategies. This review will highlight key concepts in cancer immunotherapy and illustrate immune principles and strategies that have been or could be used to help destroy MDR positive tumor cells, either alone or in rational combinations.Immunotherapy: A useful strategy to help combat multidrug resistanceTyler J. Curiel10.1016/j.drup.2012.03.003Drug Resistance Updates 15, 1 (2012)2012-04-09Drug Resistance Updates2012-04-09151-2S1368-7646(12)X0002-5Reviews106113http://www.drupjournal.com/article/PIIS1368764612000052/abstract?rss=yesAbstract: The selection of chemotherapy drugs is based on the cytotoxicity to specific tumor cell types and the relatively low toxicity to normal cells and tissues. However, the toxicity to normal cells poses a major clinical challenge, particularly when malignant cells have acquired resistance to chemotherapy. This drug resistance of cancer cells results from multiple factors including individual variation, genetic heterogeneity within a tumor, and cellular evolution. Much progress in the understanding of tumor cell resistance has been made in the past 35 years, owing to milestone discoveries such as the identification and characterization of ABC transporters. Nonetheless, the complexity of the genetic and epigenetic rewiring of cancer cells makes drug resistance an equally complex phenomenon that is difficult to overcome. In this review, we discuss how the remarkable changes in the levels of glucose, IGF-I, IGFBP-1 and in other proteins caused by fasting have the potential to improve the efficacy of chemotherapy against tumors by protecting normal cells and tissues and possibly by diminishing multidrug resistance in malignant cells.Starvation, detoxification, and multidrug resistance in cancer therapyChanghan Lee, Lizzia Raffaghello, Valter D. Longo10.1016/j.drup.2012.01.004Drug Resistance Updates 15, 1 (2012)2012-03-05Drug Resistance Updates2012-03-05151-2S1368-7646(12)X0002-5Reviews114122http://www.drupjournal.com/article/PIIS1368764612000039/abstract?rss=yesAbstract: Innate or acquired resistance to cancer therapeutics remains an important area of biomedical investigation that has clear ramifications for improving cancer specific death rates. Importantly, clues to key resistance mechanisms may lie in the well-orchestrated and highly conserved cellular and systemic responses to injury and stress. Many anti-neoplastic therapies typically rely on DNA damage, which engages potent DNA damage response signaling pathways that culminate in apoptosis or growth arrest at checkpoints to allow for damage repair. However, an alternative cellular response, senescence, can also be initiated when challenged with these internal/external pressures and in ideal situations acts as a self-protecting mechanism. Senescence-induction therapies are an attractive concept in that they represent a normal, highly conserved and commonly invoked tumor-suppressing response to overwhelming genotoxic stress or oncogene activation. Yet, such approaches should ensure that senescence by-pass or senescence re-emergence does not occur, as emergent cells appear to have highly drug resistant phenotypes. Further, cell non-autonomous senescence responses may contribute to therapy-resistance in certain circumstances. Here we provide an overview of mechanisms by which cellular senescence plausibly contributes to therapy resistance and concepts by which senescence responses can be influenced to improve cancer treatment outcomes.Cellular senescence and cancer chemotherapy resistanceRyan R. Gordon, Peter S. Nelson10.1016/j.drup.2012.01.002Drug Resistance Updates 15, 1 (2012)2012-02-27Drug Resistance Updates2012-02-27151-2S1368-7646(12)X0002-5Reviews123131